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Zhang R, Wu Z, Wang H, Ji M, Shen T, Yang L, Li Y, Yu J, Huang Y, Li L, Xu Z, Sheng Y, Li X, Wang F, Xiao W. Structural optimization and pharmacological evaluation of diphenyl amine esters as anti-hepatocellular carcinoma agents by targeting TAR RNA-binding protein 2. Eur J Med Chem 2025; 291:117676. [PMID: 40279767 DOI: 10.1016/j.ejmech.2025.117676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 04/21/2025] [Accepted: 04/22/2025] [Indexed: 04/29/2025]
Abstract
Hepatocellular Carcinoma (HCC), a leading cause of cancer-related death in the world, urgently requires novel therapeutic strategies and drug targets. The TRBP-Dicer complex plays a critical role in miRNA biosynthesis, which can be regulated by small molecules to exert anti-cancer effects. This study presented the structural modification of the natural product (-)-Gomisin M1(GM), resulting in the synthesis of 37 derivatives with a diphenyl amine ester scaffold. Several of these derivatives exhibited enhanced modulation of miRNA biogenesis compared to GM. Notably, derivative 13j displayed improved binding affinity to TRBP and greater efficacy in modulating miRNA biosynthesis, as well as anti-HCC activity in vitro and in vivo. Further investigation revealed that 13j induced apoptosis and pyroptosis while inhibiting the epithelial-to-mesenchymal transition process in HCC cells. In terms of druggability, 13j possesses favorable drug-likeness and a promising safety profile. These findings provide a promising scaffold with potent activity and low toxicity, offering a foundation for the development of miRNA-based therapeutic strategies for HCC.
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Affiliation(s)
- Ruihan Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Zhao Wu
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hairong Wang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Minghui Ji
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Tianze Shen
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Linhan Yang
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yiming Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Jialing Yu
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yinqiao Huang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Lingyu Li
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zihan Xu
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Yuwen Sheng
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China
| | - Xiaoli Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Fei Wang
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China.
| | - Weilie Xiao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China.
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Silvia Lima RQD, Vasconcelos CFM, Gomes JPA, Bezerra de Menezes EDS, de Oliveira Silva B, Montenegro C, Paiva Júnior SDSL, Pereira MC. miRNA-21, an oncomiR that regulates cell proliferation, migration, invasion and therapy response in lung cancer. Pathol Res Pract 2024; 263:155601. [PMID: 39413459 DOI: 10.1016/j.prp.2024.155601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 09/10/2024] [Accepted: 09/24/2024] [Indexed: 10/18/2024]
Abstract
Lung cancer is the leading cause of cancer-related death globally, with poor survival rates due mostly to a lack of early detection. The usual diagnostic technique includes a biopsy, which is frequently performed later in the disease's progression. In order to uncover processes that improve illness detection and prognosis, miRNA-21 emerges as a major miRNA identified in a variety of cancer types, including lung cancer. This review compiles insights into the involvement of miRNA-21 within the distinct cellular processes underlying lung cancer. To achieve this, we conducted an extensive literature review, drawing from published in vitro, in vivo and clinical trials studies. Searches were performed in the PubMed, Scielo, CAPES Journal Portal, BVS, INCA, and Clinical Trials.Gov. Only English written articles were selected. As screening criteria, we selected articles that explored the modulation pathways of miRNA-21, along with the proteins and genes implicated in tumorigenesis, metastasis, therapy resistance to established treatments, and their significance in the diagnosis and prognosis of lung cancer. A total of 3294 articles were identified, and 37 papers were selected to compose the review, after analysing selection criteria. Of these, 57 % studies presented in vitro evaluation, 22 % studies showed in vivo analysis, and 12 clinical trials were found. This study elucidates the principal signaling pathways influenced by miRNA-21, which play a pivotal role in lung cancer development. This comprehensive review sheds light on the potential significance of miRNA-21 as a critical mechanism for improving the prognosis of lung cancer patients, facilitating the transition of experimental data into the clinical phase. Therefore, we summarized published articles of miRNA-21 modulated signal pathways in lung cancer.
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Affiliation(s)
| | | | - João Pedro Alves Gomes
- Research Center for Therapeutic Innovation Suely Galdino, Federal University of Pernambuco, Recife, Brazil
| | | | - Barbara de Oliveira Silva
- Research Center for Therapeutic Innovation Suely Galdino, Federal University of Pernambuco, Recife, Brazil
| | - Claudio Montenegro
- Research Center for Therapeutic Innovation Suely Galdino, Federal University of Pernambuco, Recife, Brazil
| | | | - Michelly Cristiny Pereira
- Research Center for Therapeutic Innovation Suely Galdino, Federal University of Pernambuco, Recife, Brazil.
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3
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Jurj A, Fontana B, Varani G, Calin GA. Small molecules targeting microRNAs: new opportunities and challenges in precision cancer therapy. Trends Cancer 2024; 10:809-824. [PMID: 39107162 PMCID: PMC11961049 DOI: 10.1016/j.trecan.2024.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 06/17/2024] [Accepted: 06/20/2024] [Indexed: 08/09/2024]
Abstract
Noncoding RNAs, especially miRNAs, play a pivotal role in cancer initiation and metastasis, underscoring their susceptibility to precise modulation via small molecule inhibitors. This review examines the innovative strategy of targeting oncogenic miRNAs with small drug-like molecules, an approach that can reshape the cancer treatment landscape. We review the current understanding of the multifaceted roles of miRNAs in oncogenesis, highlighting emerging therapeutic paradigms that have the potential to expand cancer treatment options. As research on small molecule inhibitors of miRNA is still in its early stages, ongoing investigative efforts and the development of new technologies and chemical matter are essential to fulfill the significant potential of this innovative approach to cancer treatment.
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Affiliation(s)
- Ancuta Jurj
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Beatrice Fontana
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Gabriele Varani
- Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Zhou Y, Chen SJ. Advances in machine-learning approaches to RNA-targeted drug design. ARTIFICIAL INTELLIGENCE CHEMISTRY 2024; 2:100053. [PMID: 38434217 PMCID: PMC10904028 DOI: 10.1016/j.aichem.2024.100053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2024]
Abstract
RNA molecules play multifaceted functional and regulatory roles within cells and have garnered significant attention in recent years as promising therapeutic targets. With remarkable successes achieved by artificial intelligence (AI) in different fields such as computer vision and natural language processing, there is a growing imperative to harness AI's potential in computer-aided drug design (CADD) to discover novel drug compounds that target RNA. Although machine-learning (ML) approaches have been widely adopted in the discovery of small molecules targeting proteins, the application of ML approaches to model interactions between RNA and small molecule is still in its infancy. Compared to protein-targeted drug discovery, the major challenges in ML-based RNA-targeted drug discovery stem from the scarcity of available data resources. With the growing interest and the development of curated databases focusing on interactions between RNA and small molecule, the field anticipates a rapid growth and the opening of a new avenue for disease treatment. In this review, we aim to provide an overview of recent advancements in computationally modeling RNA-small molecule interactions within the context of RNA-targeted drug discovery, with a particular emphasis on methodologies employing ML techniques.
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Affiliation(s)
- Yuanzhe Zhou
- Department of Physics and Astronomy, University of Missouri, Columbia, MO 65211-7010, USA
| | - Shi-Jie Chen
- Department of Physics and Astronomy, Department of Biochemistry, Institute of Data Sciences and Informatics, University of Missouri, Columbia, MO 65211-7010, USA
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Nagasawa R, Onizuka K, Komatsu KR, Miyashita E, Murase H, Ojima K, Ishikawa S, Ozawa M, Saito H, Nagatsugi F. Large-scale analysis of small molecule-RNA interactions using multiplexed RNA structure libraries. Commun Chem 2024; 7:98. [PMID: 38693284 PMCID: PMC11865577 DOI: 10.1038/s42004-024-01181-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 04/17/2024] [Indexed: 05/03/2024] Open
Abstract
The large-scale analysis of small-molecule binding to diverse RNA structures is key to understanding the required interaction properties and selectivity for developing RNA-binding molecules toward RNA-targeted therapies. Here, we report a new system for performing the large-scale analysis of small molecule-RNA interactions using a multiplexed pull-down assay with RNA structure libraries. The system profiled the RNA-binding landscapes of G-clamp and thiazole orange derivatives, which recognizes an unpaired guanine base and are good probes for fluorescent indicator displacement (FID) assays, respectively. We discuss the binding preferences of these molecules based on their large-scale affinity profiles. In addition, we selected combinations of fluorescent indicators and different ranks of RNA based on the information and screened for RNA-binding molecules using FID. RNAs with high- and intermediate-rank RNA provided reliable results. Our system provides fundamental information about small molecule-RNA interactions and facilitates the discovery of novel RNA-binding molecules.
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Affiliation(s)
- Ryosuke Nagasawa
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Miyagi, 980-8577, Japan
- Department of Chemistry, Graduate School of Science, Tohoku University, Miyagi, 980-8578, Japan
| | - Kazumitsu Onizuka
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Miyagi, 980-8577, Japan.
- Department of Chemistry, Graduate School of Science, Tohoku University, Miyagi, 980-8578, Japan.
- Division for the Establishment of Frontier Sciences of Organization for Advanced Studies, Tohoku University, Miyagi, 980-8577, Japan.
| | - Kaoru R Komatsu
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan
| | - Emi Miyashita
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan
| | - Hirotaka Murase
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Miyagi, 980-8577, Japan
| | - Kanna Ojima
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Miyagi, 980-8577, Japan
- Department of Chemistry, Graduate School of Science, Tohoku University, Miyagi, 980-8578, Japan
| | - Shunya Ishikawa
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Miyagi, 980-8577, Japan
- Department of Chemistry, Graduate School of Science, Tohoku University, Miyagi, 980-8578, Japan
| | - Mamiko Ozawa
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Miyagi, 980-8577, Japan
| | - Hirohide Saito
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
| | - Fumi Nagatsugi
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Miyagi, 980-8577, Japan.
- Department of Chemistry, Graduate School of Science, Tohoku University, Miyagi, 980-8578, Japan.
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Tadesse K, Benhamou RI. Targeting MicroRNAs with Small Molecules. Noncoding RNA 2024; 10:17. [PMID: 38525736 PMCID: PMC10961812 DOI: 10.3390/ncrna10020017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 03/07/2024] [Accepted: 03/10/2024] [Indexed: 03/26/2024] Open
Abstract
MicroRNAs (miRs) have been implicated in numerous diseases, presenting an attractive target for the development of novel therapeutics. The various regulatory roles of miRs in cellular processes underscore the need for precise strategies. Recent advances in RNA research offer hope by enabling the identification of small molecules capable of selectively targeting specific disease-associated miRs. This understanding paves the way for developing small molecules that can modulate the activity of disease-associated miRs. Herein, we discuss the progress made in the field of drug discovery processes, transforming the landscape of miR-targeted therapeutics by small molecules. By leveraging various approaches, researchers can systematically identify compounds to modulate miR function, providing a more potent intervention either by inhibiting or degrading miRs. The implementation of these multidisciplinary approaches bears the potential to revolutionize treatments for diverse diseases, signifying a significant stride towards the targeting of miRs by precision medicine.
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Affiliation(s)
| | - Raphael I. Benhamou
- The Institute for Drug Research of the School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
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Zheng YW, Yu SY, Li Z, Xu YT, Zhao WW, Jiang D, Chen HY, Xu JJ. High-Precision Single-Cell microRNA Therapy by a Functional Nanopipette with Sensitive Photoelectrochemical Feedback. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2307067. [PMID: 37972263 DOI: 10.1002/smll.202307067] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/15/2023] [Indexed: 11/19/2023]
Abstract
This work proposes the concept of single-cell microRNA (miR) therapy and proof-of-concept by engineering a nanopipette for high-precision miR-21-targeted therapy in a single HeLa cell with sensitive photoelectrochemical (PEC) feedback. Targeting the representative oncogenic miR-21, the as-functionalized nanopipette permits direct intracellular drug administration with precisely controllable dosages, and the corresponding therapeutic effects can be sensitively transduced by a PEC sensing interface that selectively responds to the indicator level of cytosolic caspase-3. The experimental results reveal that injection of ca. 4.4 × 10-20 mol miR-21 inhibitor, i.e., 26488 copies, can cause the obvious therapeutic action in the targeted cell. This work features a solution to obtain the accurate knowledge of how a certain miR-drug with specific dosages treats the cells and thus provides an insight into futuristic high-precision clinical miR therapy using personalized medicine, provided that the prerequisite single-cell experiments are courses of personalized customization.
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Affiliation(s)
- You-Wei Zheng
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
| | - Si-Yuan Yu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
| | - Zheng Li
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
| | - Yi-Tong Xu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
| | - Wei-Wei Zhao
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
| | - Dechen Jiang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
| | - Hong-Yuan Chen
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
| | - Jing-Juan Xu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
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Singh RR, Mondal I, Janjua T, Popat A, Kulshreshtha R. Engineered smart materials for RNA based molecular therapy to treat Glioblastoma. Bioact Mater 2024; 33:396-423. [PMID: 38059120 PMCID: PMC10696434 DOI: 10.1016/j.bioactmat.2023.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 10/19/2023] [Accepted: 11/14/2023] [Indexed: 12/08/2023] Open
Abstract
Glioblastoma (GBM) is an aggressive malignancy of the central nervous system (CNS) that remains incurable despite the multitude of improvements in cancer therapeutics. The conventional chemo and radiotherapy post-surgery have only been able to improve the prognosis slightly; however, the development of resistance and/or tumor recurrence is almost inevitable. There is a pressing need for adjuvant molecular therapies that can successfully and efficiently block tumor progression. During the last few decades, non-coding RNAs (ncRNAs) have emerged as key players in regulating various hallmarks of cancer including that of GBM. The levels of many ncRNAs are dysregulated in cancer, and ectopic modulation of their levels by delivering antagonists or overexpression constructs could serve as an attractive option for cancer therapy. The therapeutic potential of several types of ncRNAs, including miRNAs, lncRNAs, and circRNAs, has been validated in both in vitro and in vivo models of GBM. However, the delivery of these RNA-based therapeutics is highly challenging, especially to the tumors of the brain as the blood-brain barrier (BBB) poses as a major obstacle, among others. Also, since RNA is extremely fragile in nature, careful considerations must be met while designing a delivery agent. In this review we have shed light on how ncRNA therapy can overcome the limitations of its predecessor conventional therapy with an emphasis on smart nanomaterials that can aide in the safe and targeted delivery of nucleic acids to treat GBM. Additionally, critical gaps that currently exist for successful transition from viral to non-viral vector delivery systems have been identified. Finally, we have provided a perspective on the future directions, potential pathways, and target areas for achieving rapid clinical translation of, RNA-based macromolecular therapy to advance the effective treatment of GBM and other related diseases.
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Affiliation(s)
- Ravi Raj Singh
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
- University of Queensland –IIT Delhi Academy of Research (UQIDAR)
| | - Indranil Mondal
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
| | - Taskeen Janjua
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Amirali Popat
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
- Department of Functional Materials and Catalysis, Faculty of Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria
| | - Ritu Kulshreshtha
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
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Mattoo S, Gupta A, Chauhan M, Agrawal A, Pore SK. Prospects and challenges of noncoding-RNA-mediated inhibition of heat shock protein 90 for cancer therapy. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2024; 1867:195006. [PMID: 38218528 DOI: 10.1016/j.bbagrm.2024.195006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 01/06/2024] [Accepted: 01/08/2024] [Indexed: 01/15/2024]
Abstract
Heat Shock Protein 90 (HSP90) is a potential drug target for cancer therapy as it is often dysregulated in several cancers, including lung, breast, pancreatic, and prostate cancers. In cancer, HSP90 fails to maintain the structural and functional integrity of its several client proteins which are involved in the hallmarks of cancer such as cell proliferation, invasion, migration, angiogenesis, and apoptosis. Several small molecule inhibitors of HSP90 have been shown to exhibit anticancer effects in vitro and in vivo animal models. However, a few of them are currently under clinical studies. The status and potential limitations of these inhibitors are discussed here. Studies demonstrate that several noncoding RNAs (ncRNAs) such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) regulate HSP90 and its client proteins to modulate cellular processes to exhibit oncogenic or tumor suppressing properties. Over the last decade, miRNAs and lncRNAs have drawn significant interest from the scientific community as therapeutic agents or targets for clinical applications. Here, we discuss the detailed mechanistic regulation of HSP90 and its client proteins by ncRNAs. Moreover, we highlight the significance of these ncRNAs as potential therapeutic agents/targets, and the challenges associated with ncRNA-based therapies. This article aims to provide a holistic view on HSP90-regulating ncRNAs for the development of novel therapeutic strategies to combat cancer.
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Affiliation(s)
- Shria Mattoo
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University Uttar Pradesh, Noida 201311, India
| | - Abha Gupta
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University Uttar Pradesh, Noida 201311, India
| | - Manvee Chauhan
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University Uttar Pradesh, Noida 201311, India
| | - Akshi Agrawal
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida 201311, India
| | - Subrata Kumar Pore
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University Uttar Pradesh, Noida 201311, India.
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Seyhan AA. Trials and Tribulations of MicroRNA Therapeutics. Int J Mol Sci 2024; 25:1469. [PMID: 38338746 PMCID: PMC10855871 DOI: 10.3390/ijms25031469] [Citation(s) in RCA: 85] [Impact Index Per Article: 85.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/15/2024] [Accepted: 01/17/2024] [Indexed: 02/12/2024] Open
Abstract
The discovery of the link between microRNAs (miRNAs) and a myriad of human diseases, particularly various cancer types, has generated significant interest in exploring their potential as a novel class of drugs. This has led to substantial investments in interdisciplinary research fields such as biology, chemistry, and medical science for the development of miRNA-based therapies. Furthermore, the recent global success of SARS-CoV-2 mRNA vaccines against the COVID-19 pandemic has further revitalized interest in RNA-based immunotherapies, including miRNA-based approaches to cancer treatment. Consequently, RNA therapeutics have emerged as highly adaptable and modular options for cancer therapy. Moreover, advancements in RNA chemistry and delivery methods have been pivotal in shaping the landscape of RNA-based immunotherapy, including miRNA-based approaches. Consequently, the biotechnology and pharmaceutical industry has witnessed a resurgence of interest in incorporating RNA-based immunotherapies and miRNA therapeutics into their development programs. Despite substantial progress in preclinical research, the field of miRNA-based therapeutics remains in its early stages, with only a few progressing to clinical development, none reaching phase III clinical trials or being approved by the US Food and Drug Administration (FDA), and several facing termination due to toxicity issues. These setbacks highlight existing challenges that must be addressed for the broad clinical application of miRNA-based therapeutics. Key challenges include establishing miRNA sensitivity, specificity, and selectivity towards their intended targets, mitigating immunogenic reactions and off-target effects, developing enhanced methods for targeted delivery, and determining optimal dosing for therapeutic efficacy while minimizing side effects. Additionally, the limited understanding of the precise functions of miRNAs limits their clinical utilization. Moreover, for miRNAs to be viable for cancer treatment, they must be technically and economically feasible for the widespread adoption of RNA therapies. As a result, a thorough risk evaluation of miRNA therapeutics is crucial to minimize off-target effects, prevent overdosing, and address various other issues. Nevertheless, the therapeutic potential of miRNAs for various diseases is evident, and future investigations are essential to determine their applicability in clinical settings.
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Affiliation(s)
- Attila A. Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA;
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI 02912, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02912, USA
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11
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Abaturov A, Babуch V. Drug regulation of microRNA. CHILD`S HEALTH 2024; 18:572-583. [DOI: 10.22141/2224-0551.18.8.2023.1657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The scientific review provides the mechanisms of drug regulation of microRNA in the human body. To write the article, information was searched using Scopus, Web of Science, MEDLINE, PubMed, Google Scholar, Embase, Global Health, The Cochrane Library databases. To restore the reduced functional activity of microRNAs, replacement therapy is used, with modified synthetic analogs of endogenous microRNAs, and drugs that enhance the production of the body’s own microRNAs. The authors state that numerous studies have confirmed the effectiveness of miRNA replacement therapy. It is known that there are several groups of drugs among miRNA inhibitors: anti-miRNA oligonucleotides, miRNA traps, miRNA mimics that prevent miRNA binding; peptide nucleic acids, small-molecule inhibitors. The authors suggest that the expression of drug-metabolizing enzymes is controlled by nuclear receptors and transcription factors, epigenetic regulation such as DNA methylation and histone acetylation, and post-translational modification. It is emphasized that ursodeoxycholic acid modulates the expression of some miRNAs. It is known that probiotic bacteria can modulate the expression level of miRNA genes. The use of probiotics is accompanied by a change in the expression of numerous genes of the body involved in the regulation of the inflammatory response, allergic reactions, metabolism and other biological processes. Thus, modern science is intensively studying the potential of using drugs that restore miRNA content or inhibit miRNA activity for the therapy of miRNA-dependent conditions. The results of scientific research confirmed the therapeutic effect of ursodeoxycholic acid and probiotic preparations due to the effect on the activity of miRNA generation in hepatobiliary diseases. Therefore, the introduction into clinical practice of drugs than can modulate the content and expression of specific miRNAs will certainly open new perspectives in the treatment of patients with hepatobiliary diseases.
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12
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Qu J, Song Z, Cheng X, Jiang Z, Zhou J. Neighborhood-based inference and restricted Boltzmann machine for small molecule-miRNA associations prediction. PeerJ 2023; 11:e15889. [PMID: 37641598 PMCID: PMC10460564 DOI: 10.7717/peerj.15889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 07/21/2023] [Indexed: 08/31/2023] Open
Abstract
Background A growing number of experiments have shown that microRNAs (miRNAs) can be used as target of small molecules (SMs) to regulate gene expression for treating diseases. Therefore, identifying SM-related miRNAs is helpful for the treatment of diseases in the domain of medical investigation. Methods This article presents a new computational model, called NIRBMSMMA (neighborhood-based inference (NI) and restricted Boltzmann machine (RBM)), which we developed to identify potential small molecule-miRNA associations (NIRBMSMMA). First, grounded on known SM-miRNAs associations, SM similarity and miRNA similarity, NI was used to predict score of an unknown SM-miRNA pair by reckoning the sum of known associations between neighbors of the SM (miRNA) and the miRNA (SM). Second, utilizing a two-layered generative stochastic artificial neural network, RBM was used to predict SM-miRNA association by learning potential probability distribution from known SM-miRNA associations. At last, an ensemble learning model was conducted to combine NI and RBM for identifying potential SM-miRNA associations. Results Furthermore, we conducted global leave one out cross validation (LOOCV), miRNA-fixed LOOCV, SM-fixed LOOCV and five-fold cross validation to assess performance of NIRBMSMMA based on three datasets. Results showed that NIRBMSMMA obtained areas under the curve (AUC) of 0.9912, 0.9875, 0.8376 and 0.9898 ± 0.0009 under global LOOCV, miRNA-fixed LOOCV, SM-fixed LOOCV and five-fold cross validation based on dataset 1, respectively. For dataset 2, the AUCs are 0.8645, 0.8720, 0.7066 and 0.8547 ± 0.0046 in turn. For dataset 3, the AUCs are 0.9884, 0.9802, 0.8239 and 0.9870 ± 0.0015 in turn. Also, we conducted case studies to further assess the predictive performance of NIRBMSMMA. These results illustrated the proposed model is a useful tool in predicting potential SM-miRNA associations.
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Affiliation(s)
- Jia Qu
- School of Computer Science and Artificial Intelligence, Changzhou University, Changzhou, Jiangsu, China
| | - Zihao Song
- School of Computer Science and Artificial Intelligence, Changzhou University, Changzhou, Jiangsu, China
| | - Xiaolong Cheng
- School of Computer Science and Artificial Intelligence, Changzhou University, Changzhou, Jiangsu, China
| | - Zhibin Jiang
- Department of Computer Science and Engineering, Shaoxing University, Shaoxing, Zhejiang, China
| | - Jie Zhou
- Department of Computer Science and Engineering, Shaoxing University, Shaoxing, Zhejiang, China
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13
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Shortridge MD, Chaubey B, Zhang HJ, Pavelitz T, Vidadala V, Tang C, Olsen GL, Calin GA, Varani G. Drug-Like Small Molecules That Inhibit Expression of the Oncogenic MicroRNA-21. ACS Chem Biol 2023; 18:237-250. [PMID: 36727622 PMCID: PMC10593481 DOI: 10.1021/acschembio.2c00502] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
We report the discovery of drug-like small molecules that bind specifically to the precursor of the oncogenic and pro-inflammatory microRNA-21 with mid-nanomolar affinity. The small molecules target a local structure at the Dicer cleavage site and induce distinctive structural changes in the RNA, which correlate with specific inhibition of miRNA processing. Structurally conservative single nucleotide substitutions eliminate the conformational change induced by the small molecules, which is also not observed in other miRNA precursors. The most potent of these compounds reduces cellular proliferation and miR-21 levels in cancer cell lines without inhibiting kinases or classical receptors, while closely related compounds without this specific binding activity are inactive in cells. These molecules are highly ligand-efficient (MW < 330) and display specific biochemical and cellular activity by suppressing the maturation of miR-21, thereby providing an avenue toward therapeutic development in multiple diseases where miR-21 is abnormally expressed.
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Affiliation(s)
- Matthew D Shortridge
- Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
| | - Bhawna Chaubey
- Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
| | - Huanyu J Zhang
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
| | - Thomas Pavelitz
- Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
| | - Venkata Vidadala
- Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
| | - Changyan Tang
- Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
| | - Gregory L Olsen
- Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
| | - George A Calin
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
| | - Gabriele Varani
- Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
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14
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Izadi Z, Barzegari E, Iranpanah A, Sajadimajd S, Derakhshankhah H. Gentamycin Rationally Repositioned to Inhibit miR-34a Ameliorates Oxidative Injury to PC12 Cells. ACS OMEGA 2023; 8:771-781. [PMID: 36643496 PMCID: PMC9835649 DOI: 10.1021/acsomega.2c06112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/08/2022] [Indexed: 06/17/2023]
Abstract
Ischemic stroke accompanies oxidative stress and cell death in the cerebral tissue. The microRNA miR-34a plays a pivotal role in this molecular pathology. This study presents the rational repositioning of aminoglycosidic antibiotics as miR-34a antagonists in order to assess their efficiency in protecting the PC12 stroke model cells from oxidative stress occurring under cerebral ischemic conditions. A library of 29 amino-sugar compounds were screened against anticipated structural models of miR-34a through molecular docking. MiR-ligand interactions were mechanistically studied by molecular dynamics simulations and free-energy calculations. Cultured PC12 cells were treated by H2O2 alone or in combination with gentamycin and neomycin as selected drugs. Cell viability and apoptosis were detected by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) and annexin V-FITC/propidium iodate (PI) double staining assays, respectively. The expression levels of key factors involved in cell proliferation, oxidative stress, and apoptosis in treated PC12 cells were measured through a quantitative real-time polymerase chain reaction and flow cytometric annexin V-FITC/PI double staining assays. A stable and energetically favorable binding was observed for miR-34a with gentamycin and neomycin. Gentamycin pretreatments followed by H2O2 oxidative injury led to increased cell viability and protected PC12 cells against H2O2-induced apoptotic events. This study will help in further understanding how the suppression of miR-34a in neural tissue affects the cell viability upon stroke.
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Affiliation(s)
- Zhila Izadi
- Pharmaceutical
Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran
- USERN
Office, Kermanshah University of Medical
Sciences, Kermanshah 6715847141, Iran
| | - Ebrahim Barzegari
- Medical
Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran
| | - Amin Iranpanah
- Pharmaceutical
Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran
- USERN
Office, Kermanshah University of Medical
Sciences, Kermanshah 6715847141, Iran
| | - Soraya Sajadimajd
- Department
of Biology, Faculty of Science, Razi University, Kermanshah 67144-14971, Iran
| | - Hossein Derakhshankhah
- Pharmaceutical
Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran
- USERN
Office, Kermanshah University of Medical
Sciences, Kermanshah 6715847141, Iran
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15
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Fu P, Chen H, Ouyang L, Li L, Wang Y, Qian S, Cao Z, Wu K, Chao J, Zheng J. DNA Nanoribbon for Efficient Anti-miRNA Peptide Nucleic Acid Delivery and Synergistic Enhancement of Cancer Cell Apoptosis. Anal Chem 2022; 95:1811-1816. [PMID: 36542541 DOI: 10.1021/acs.analchem.2c04760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Antisense peptide nucleic acid (asPNA), an effective antisense drug, has been employed as a gene therapy agent and a useful tool in molecular biology. Gaining control over the delivery of asPNA to target tissues has been a major hindrance to its wide application in clinical practice. A simple and efficient DNA nanoribbon (DNR)-based drug delivery process has been designed in this study that releases the asPNA agent to inhibit oncogenic microRNAs (miRNAs). Furthermore, we demonstrated how the AS1411 aptamer that binds nucleolin on the cell membranes works as a control mechanism capable of identifying target cancer cells and enhancing the enrichment capacity of DNR. With the biodegradability of DNR, we can efficiently initiate the release of asPNA into the cytoplasm, particularly targeting the intended miR-21 and synergistically increasing programmed cell death 4 (PDCD4) expression to enhance cell apoptosis. We assume that this well-defined delivery mechanism will aid in designing antisense site-specific treatments for various diseases, including cancer.
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Affiliation(s)
- Pan Fu
- Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, P. R. China
| | - Hao Chen
- Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, P. R. China
| | - Lilin Ouyang
- State Key Laboratory of Organic Electronics and Information Displays and Jiangsu Key Laboratory for Biosensors, Nanjing University of Posts and Telecommunications, Nanjing 210023, China
| | - Lin Li
- Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, P. R. China
| | - Yuhui Wang
- Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, P. R. China
| | - Sihua Qian
- Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, P. R. China
| | - Zhanglei Cao
- Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, P. R. China
| | - Kerong Wu
- Ningbo First Hospital, Ningbo, Zhejiang 315000, P. R. China
| | - Jie Chao
- State Key Laboratory of Organic Electronics and Information Displays and Jiangsu Key Laboratory for Biosensors, Nanjing University of Posts and Telecommunications, Nanjing 210023, China
| | - Jianping Zheng
- Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, P. R. China
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16
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Chaudhry T, Coxon CR, Ross K. Trading places: Peptide and small molecule alternatives to oligonucleotide-based modulation of microRNA expression. Drug Discov Today 2022; 27:103337. [PMID: 35995360 DOI: 10.1016/j.drudis.2022.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 06/13/2022] [Accepted: 08/09/2022] [Indexed: 11/03/2022]
Abstract
It is well established that microRNA (miRNA) dysregulation is involved in the development and progression of various diseases, especially cancer. Emerging evidence suggests that small molecule and peptide agents can interfere with miRNA disease pathways. Despite this, very little is known about structural features that drive drug-miRNA interactions and subsequent inhibition. In this review, we highlight the advances made in the development of small molecule and peptide inhibitors of miRNA processing. Specifically, we attempt to draw attention to peptide features that may be critical for interaction with the miRNA secondary structure to regulate miRNA expression. We hope that this review will help to establish peptides as exciting miRNA expression modulators and will contribute towards the development of the first miRNA-targeting peptide therapy.
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Affiliation(s)
- Talhat Chaudhry
- School of Pharmacy and Biomolecular Science, Liverpool John Moores University, Liverpool, UK; Institute for Health Research, Liverpool John Moores University, Liverpool, UK
| | - Christopher R Coxon
- EaStChem School of Chemistry, The University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh EH14 4AS, UK
| | - Kehinde Ross
- School of Pharmacy and Biomolecular Science, Liverpool John Moores University, Liverpool, UK; Institute for Health Research, Liverpool John Moores University, Liverpool, UK.
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17
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Xi XX, Hei YY, Guo Y, Zhao HY, Xin M, Lu S, Jiang C, Zhang SQ. Identification of benzamides derivatives of norfloxacin as promising microRNA-21 inhibitors via repressing its transcription. Bioorg Med Chem 2022; 66:116803. [PMID: 35561631 DOI: 10.1016/j.bmc.2022.116803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 05/01/2022] [Accepted: 05/02/2022] [Indexed: 11/29/2022]
Abstract
MicroRNA-21 is a carcinogenic microRNA, whose overexpression arises in a variety of tumor tissues. Hence, microRNA-21 a prospective target for cancer treatment, and regulation of microRNA-21 by small molecule inhibitors is deemed as a promising approach for tumor therapy. In this work, to discover potent microRNA-21 inhibitor, series of 4-(N-norfloxacin-acyl)aminobenzamides were designed and synthesized, and their inhibitory effects were appraised by utilizing dual luciferase reporter assays. The results indicated that compound A7 was the most efficient microRNA-21 small molecule inhibitor. What's more, A7 suppressed the migration of Hela cells and the colony formation of Hela and HCT-116 cells as well as promoted apoptosis of Hela cells. In the mechanism study, results of RT-qPCR certified that A7 could reduce the level of mature microRNA-21 via disrupting its expression at the transcriptional level of its primary form "pri-miR-21", which was distinct from most previous inhibitors directly binding with pre-miR-21. Noticeably, Western blotting and RT-qPCR uncovered A7 could upregulate the expression PTEN, EGR1 and SLIT2, which are the downstream functional targets of microRNA-21. These findings demonstrated that A7 was a promising microRNA-21 small molecule inhibitor and 4-(N-norfloxacin-acyl) aminobenzamide can serve as a new scaffold for discovery of potent microRNA-21 inhibitor.
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Affiliation(s)
- Xiao-Xiao Xi
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Yuan-Yuan Hei
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Yuanxu Guo
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Hong-Yi Zhao
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Minhang Xin
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Shemin Lu
- National Regional Children's Medical Center (Northwest), Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi'an Key Laboratory of Children's Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710003, PR China; Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Congshan Jiang
- National Regional Children's Medical Center (Northwest), Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi'an Key Laboratory of Children's Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710003, PR China; Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi 710061, PR China.
| | - San-Qi Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi 710061, PR China.
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18
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Yardım-Akaydin S, Karahalil B, Nacak Baytas S. New therapy strategies in the management of breast cancer. Drug Discov Today 2022; 27:1755-1762. [PMID: 35337961 DOI: 10.1016/j.drudis.2022.03.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 02/13/2022] [Accepted: 03/20/2022] [Indexed: 12/19/2022]
Abstract
Breast cancer (BC), the second leading cause of cancer-related deaths after lung cancer, is the most common cancer type among women worldwide. BC comprises multiple subtypes based on molecular properties. Depending on the type of BC, hormone therapy, targeted therapy, and immunotherapy are the current systemic treatment options along with conventional chemotherapy. Several new molecular targets, miRNAs, and long non-coding RNAs (lncRNAs), have been discovered over the past few decades and are powerful potential therapeutic targets. Here, we review advanced therapeutics as new players in BC management.
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Affiliation(s)
- Sevgi Yardım-Akaydin
- Department of Biochemistry, Faculty of Pharmacy, Gazi University, 06330-Ankara, Turkey
| | - Bensu Karahalil
- Department of Toxicology, Faculty of Pharmacy, Gazi University, 06330-Ankara, Turkey
| | - Sultan Nacak Baytas
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330-Ankara, Turkey.
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19
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Hei YY, Wang S, Xi XX, Wang HP, Guo Y, Xin M, Jiang C, Lu S, Zhang SQ. Design, synthesis, and evaluation of fluoroquinolone derivatives as MicroRNA-21 small-molecule inhibitors. J Pharm Anal 2022; 12:653-663. [PMID: 36105166 PMCID: PMC9463491 DOI: 10.1016/j.jpha.2021.12.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 12/31/2021] [Accepted: 12/31/2021] [Indexed: 01/10/2023] Open
Abstract
MicroRNA-21 (miRNA-21) is highly expressed in various tumors. Small-molecule inhibition of miRNA-21 is considered to be an attractive novel cancer therapeutic strategy. In this study, fluoroquinolone derivatives A1–A43 were synthesized and used as miRNA-21 inhibitors. Compound A36 showed the most potent inhibitory activity and specificity for miRNA-21 in a dual-luciferase reporter assay in HeLa cells. Compound A36 significantly reduced the expression of mature miRNA-21 and increased the protein expression of miRNA-21 target genes, including programmed cell death protein 4 (PDCD4) and phosphatase and tensin homology deleted on chromosome ten (PTEN), at 10 μM in HeLa cells. The Cell Counting Kit-8 assay (CCK-8) was used to evaluate the antiproliferative activity of A36; the results showed that the IC50 value range of A36 against six tumor cell lines was between 1.76 and 13.0 μM. Meanwhile, A36 did not display cytotoxicity in BEAS-2B cells (lung epithelial cells from a healthy human donor). Furthermore, A36 significantly induced apoptosis, arrested cells at the G0/G1 phase, and inhibited cell-colony formation in HeLa cells. In addition, mRNA deep sequencing showed that treatment with A36 could generate 171 dysregulated mRNAs in HeLa cells, while the expression of miRNA-21 target gene dual-specificity phosphatase 5 (DUSP5) was significantly upregulated at both the mRNA and protein levels. Collectively, these findings demonstrated that A36 is a novel miRNA-21 inhibitor.
Fluoroquinolone derivatives A1–A43 were synthesized and evaluated as miRNA-21 small-compound inhibitors. The quinolone derivative A36 was validated as an active and specific miRNA-21 small-compound inhibitor. A36 displayed differential anti-cell proliferation activity between normal and miRNA-21-overexpressing cancer cells.
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Affiliation(s)
- Yuan-Yuan Hei
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
| | - Si Wang
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
| | - Xiao-Xiao Xi
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Hai-Peng Wang
- Department of Medical Oncology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China
| | - Yuanxu Guo
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
| | - Minhang Xin
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
| | - Congshan Jiang
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
- Corresponding author. Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
| | - Shemin Lu
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
| | - San-Qi Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
- Corresponding author. Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
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20
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Nguyen LD, Chau RK, Krichevsky AM. Small Molecule Drugs Targeting Non-Coding RNAs as Treatments for Alzheimer's Disease and Related Dementias. Genes (Basel) 2021; 12:2005. [PMID: 34946953 PMCID: PMC8701955 DOI: 10.3390/genes12122005] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 12/24/2022] Open
Abstract
Despite the enormous burden of Alzheimer's disease and related dementias (ADRD) on patients, caregivers, and society, only a few treatments with limited efficacy are currently available. While drug development conventionally focuses on disease-associated proteins, RNA has recently been shown to be druggable for therapeutic purposes as well. Approximately 70% of the human genome is transcribed into non-protein-coding RNAs (ncRNAs) such as microRNAs, long ncRNAs, and circular RNAs, which can adopt diverse structures and cellular functions. Many ncRNAs are specifically enriched in the central nervous system, and their dysregulation is implicated in ADRD pathogenesis, making them attractive therapeutic targets. In this review, we first detail why targeting ncRNAs with small molecules is a promising therapeutic strategy for ADRD. We then outline the process from discovery to validation of small molecules targeting ncRNAs in preclinical studies, with special emphasis on primary high-throughput screens for identifying lead compounds. Screening strategies for specific ncRNAs will also be included as examples. Key challenges-including selecting appropriate ncRNA targets, lack of specificity of small molecules, and general low success rate of neurological drugs and how they may be overcome-will be discussed throughout the review.
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Affiliation(s)
- Lien D Nguyen
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Rachel K Chau
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Anna M Krichevsky
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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21
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LeBlanc RM, Mesleh MF. A drug discovery toolbox for Nuclear Magnetic Resonance (NMR) characterization of ligands and their targets. DRUG DISCOVERY TODAY. TECHNOLOGIES 2021; 37:51-60. [PMID: 34895655 DOI: 10.1016/j.ddtec.2020.11.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/22/2020] [Accepted: 11/27/2020] [Indexed: 10/22/2022]
Abstract
Information about the structure, dynamics, and ligand-binding properties of biomolecules can be derived from Nuclear Magnetic Resonance (NMR) spectroscopy and provides valuable information for drug discovery. A multitude of experimental approaches provides a wealth of information that can be tailored to the system of interest. Methods to study the behavior of ligands upon target binding enable the identification of weak binders in a robust manner that is critical for the identification of truly novel binding interactions. This is particularly important for challenging targets. Observing the solution behavior of biomolecules yields information about their structure, dynamics, and interactions. This review describes the breadth of approaches that are available, many of which are under-utilized in a drug-discovery environment, and focuses on recent advances that continue to emerge.
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Affiliation(s)
- Regan M LeBlanc
- Structural Biology and Biophysics, Vertex Pharmaceuticals Inc., Boston, MA, 02210, United States
| | - Michael F Mesleh
- Structural Biology and Biophysics, Vertex Pharmaceuticals Inc., Boston, MA, 02210, United States.
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22
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Ding P, Ouyang W, Luo J, Kwoh CK. Heterogeneous information network and its application to human health and disease. Brief Bioinform 2021; 21:1327-1346. [PMID: 31566212 DOI: 10.1093/bib/bbz091] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 06/29/2019] [Accepted: 06/30/2019] [Indexed: 12/11/2022] Open
Abstract
The molecular components with the functional interdependencies in human cell form complicated biological network. Diseases are mostly caused by the perturbations of the composite of the interaction multi-biomolecules, rather than an abnormality of a single biomolecule. Furthermore, new biological functions and processes could be revealed by discovering novel biological entity relationships. Hence, more and more biologists focus on studying the complex biological system instead of the individual biological components. The emergence of heterogeneous information network (HIN) offers a promising way to systematically explore complicated and heterogeneous relationships between various molecules for apparently distinct phenotypes. In this review, we first present the basic definition of HIN and the biological system considered as a complex HIN. Then, we discuss the topological properties of HIN and how these can be applied to detect network motif and functional module. Afterwards, methodologies of discovering relationships between disease and biomolecule are presented. Useful insights on how HIN aids in drug development and explores human interactome are provided. Finally, we analyze the challenges and opportunities for uncovering combinatorial patterns among pharmacogenomics and cell-type detection based on single-cell genomic data.
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Affiliation(s)
- Pingjian Ding
- School of Computer Science, University of South China, Hengyang, China
| | - Wenjue Ouyang
- College of Computer Science and Electronic Engineering, Hunan University, Changsha, China
| | - Jiawei Luo
- College of Computer Science and Electronic Engineering, Hunan University, Changsha, China
| | - Chee-Keong Kwoh
- School of Computer Science and Engineering, Nanyang Technological University, Singapore, Singapore
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23
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Reply to Zhang and Zhu "MicroRNA Mimics or Inhibitors as Antiviral Therapeutic Approaches Against COVID-19". Drugs 2021; 81:1693-1695. [PMID: 34453691 PMCID: PMC8397847 DOI: 10.1007/s40265-021-01581-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2021] [Indexed: 11/04/2022]
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24
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Fu Z, Wang L, Li S, Chen F, Au-Yeung KKW, Shi C. MicroRNA as an Important Target for Anticancer Drug Development. Front Pharmacol 2021; 12:736323. [PMID: 34512363 PMCID: PMC8425594 DOI: 10.3389/fphar.2021.736323] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/10/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer has become the second greatest cause of death worldwide. Although there are several different classes of anticancer drugs that are available in clinic, some tough issues like side-effects and low efficacy still need to dissolve. Therefore, there remains an urgent need to discover and develop more effective anticancer drugs. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that regulate gene expression by inhibiting mRNA translation or reducing the stability of mRNA. An abnormal miRNA expression profile was found to exist widely in cancer cell, which induces limitless replicative potential and evading apoptosis. MiRNAs function as oncogenes (oncomiRs) or tumor suppressors during tumor development and progression. It was shown that regulation of specific miRNA alterations using miRNA mimics or antagomirs can normalize the gene regulatory network and signaling pathways, and reverse the phenotypes in cancer cells. The miRNA hence provides an attractive target for anticancer drug development. In this review, we will summarize the latest publications on the role of miRNA in anticancer therapeutics and briefly describe the relationship between abnormal miRNAs and tumorigenesis. The potential of miRNA-based therapeutics for anticancer treatment has been critically discussed. And the current strategies in designing miRNA targeting therapeutics are described in detail. Finally, the current challenges and future perspectives of miRNA-based therapy are conferred.
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Affiliation(s)
- Zhiwen Fu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Liu Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Shijun Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Fen Chen
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | | | - Chen Shi
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
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25
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Shortridge MD, Varani G. Efficient NMR Screening Approach to Discover Small Molecule Fragments Binding Structured RNA. ACS Med Chem Lett 2021; 12:1253-1260. [PMID: 34413954 DOI: 10.1021/acsmedchemlett.1c00109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 07/07/2021] [Indexed: 01/27/2023] Open
Abstract
We describe a scalable nuclear magnetic resonance (NMR) screening approach to identify and prioritize small molecule fragments that bind to structured RNAs. This approach is target agnostic and, therefore, amenable to many RNA structures and libraries, and it provides initial hits for further synthetic elaboration and structure-based drug discovery efforts. We demonstrate the approach on the pre-miR-21 stem-loop, which is of significant interest in oncology and metabolic diseases. We screened the pre-miR-21 hairpin using a small (420 compounds) commercially available fragment library and identified 18 hits in the first round of triage screening. This was further refined to four fragments which passed all screening cascade filters. Among these four hits, a thiadiazole fragment was demonstrated to bind the Dicer cleavage site of pre-miR-21 by target-detected NMR experiments and through the observation of clear intermolecular NOEs.
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Affiliation(s)
- Matthew D. Shortridge
- Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
| | - Gabriele Varani
- Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
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26
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Winkle M, El-Daly SM, Fabbri M, Calin GA. Noncoding RNA therapeutics - challenges and potential solutions. Nat Rev Drug Discov 2021; 20:629-651. [PMID: 34145432 PMCID: PMC8212082 DOI: 10.1038/s41573-021-00219-z] [Citation(s) in RCA: 974] [Impact Index Per Article: 243.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/27/2021] [Indexed: 02/07/2023]
Abstract
Therapeutic targeting of noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), represents an attractive approach for the treatment of cancers, as well as many other diseases. Over the past decade, substantial effort has been made towards the clinical application of RNA-based therapeutics, employing mostly antisense oligonucleotides and small interfering RNAs, with several gaining FDA approval. However, trial results have so far been ambivalent, with some studies reporting potent effects whereas others demonstrated limited efficacy or toxicity. Alternative entities such as antimiRNAs are undergoing clinical testing, and lncRNA-based therapeutics are gaining interest. In this Perspective, we discuss key challenges facing ncRNA therapeutics - including issues associated with specificity, delivery and tolerability - and focus on promising emerging approaches that aim to boost their success.
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Affiliation(s)
- Melanie Winkle
- Translational Molecular Pathology, MD Anderson Cancer Center, Texas State University, Houston, TX, USA
| | - Sherien M El-Daly
- Medical Biochemistry Department, Medical Research Division - Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences - National Research Centre, Cairo, Egypt
| | - Muller Fabbri
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - George A Calin
- Translational Molecular Pathology, MD Anderson Cancer Center, Texas State University, Houston, TX, USA.
- The RNA Interference and Non-codingRNA Center, MD Anderson Cancer Center, Texas State University, Houston, TX, USA.
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27
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Targeting RNA structures in diseases with small molecules. Essays Biochem 2021; 64:955-966. [PMID: 33078198 PMCID: PMC7724634 DOI: 10.1042/ebc20200011] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/16/2020] [Accepted: 09/30/2020] [Indexed: 01/08/2023]
Abstract
RNA is crucial for gene expression and regulation. Recent advances in understanding of RNA biochemistry, structure and molecular biology have revealed the importance of RNA structure in cellular processes and diseases. Various approaches to discovering drug-like small molecules that target RNA structure have been developed. This review provides a brief introduction to RNA structural biology and how RNA structures function as disease regulators. We summarize approaches to targeting RNA with small molecules and highlight their advantages, shortcomings and therapeutic potential.
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28
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Bush JA, Williams CC, Meyer SM, Tong Y, Haniff HS, Childs-Disney JL, Disney MD. Systematically Studying the Effect of Small Molecules Interacting with RNA in Cellular and Preclinical Models. ACS Chem Biol 2021; 16:1111-1127. [PMID: 34166593 PMCID: PMC8867596 DOI: 10.1021/acschembio.1c00014] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The interrogation and manipulation of biological systems by small molecules is a powerful approach in chemical biology. Ideal compounds selectively engage a target and mediate a downstream phenotypic response. Although historically small molecule drug discovery has focused on proteins and enzymes, targeting RNA is an attractive therapeutic alternative, as many disease-causing or -associated RNAs have been identified through genome-wide association studies. As the field of RNA chemical biology emerges, the systematic evaluation of target validation and modulation of target-associated pathways is of paramount importance. In this Review, through an examination of case studies, we outline the experimental characterization, including methods and tools, to evaluate comprehensively the impact of small molecules that target RNA on cellular phenotype.
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Affiliation(s)
- Jessica A Bush
- The Scripps Research Institute, Department of Chemistry, 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Christopher C Williams
- The Scripps Research Institute, Department of Chemistry, 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Samantha M Meyer
- The Scripps Research Institute, Department of Chemistry, 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Yuquan Tong
- The Scripps Research Institute, Department of Chemistry, 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Hafeez S Haniff
- The Scripps Research Institute, Department of Chemistry, 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Jessica L Childs-Disney
- The Scripps Research Institute, Department of Chemistry, 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Matthew D Disney
- The Scripps Research Institute, Department of Chemistry, 130 Scripps Way, Jupiter, Florida 33458, United States
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29
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Lei J, He MY, Li J, Li H, Wang W, Gopinath SCB, Xu LZ. miRNA identification by nuclease digestion in ELISA for diagnosis of osteosarcoma. Biotechnol Appl Biochem 2021; 69:1365-1372. [PMID: 34081808 DOI: 10.1002/bab.2209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 06/01/2021] [Indexed: 11/07/2022]
Abstract
Osteosarcoma is a bone cancer formed by the cells of the bone. Children, young adults, and teens are highly affected by osteosarcoma. Early identification of osteosarcoma is mandatory to improve the treatment and increase the lifespan of the patients. MicroRNA-195 (miR-195) was shown to be a suitable biomarker for osteosarcoma, and the present study describes a sensitive method of miR-195 identification by nuclease digestion in ELISA to detect and quantify the level of miR-195. S1 nuclease catalyzed endo- and exonucleolytic digestion of single-stranded (ss) RNA and DNA on ELISA polystyrene substrate, which helped to identify duplexed miR-195. This method selectively and specifically identified miR-195 without any biofouling interactions and reached the limit of detection at 10 fM within the range from 10 fM to 10 nM. Due to complete digestion of ssDNA, single- and triple-mismatched sequences failed to increase the ELISA signal, indicating specific miRNA detection. Furthermore, human serum spiked with miR-195 did not interfere with the detection, confirming selective identification. This method identified miR-195 at a lower level and will help to diagnose earlier stages of osteosarcoma.
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Affiliation(s)
- Jie Lei
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Meng-Yin He
- Department of Radiology, Wuhan Hospital Of Traditional Chinese Medicine, Wuhan, Hubei, China
| | - Jie Li
- Department of Orthopedics, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Hao Li
- First Clinical Medical College of Hubei University of Traditional Chinese Medicine, Wuhan, Hubei, China
| | - Wei Wang
- First Clinical Medical College of Hubei University of Traditional Chinese Medicine, Wuhan, Hubei, China
| | - Subash C B Gopinath
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Perlis, 01000, Malaysia.,Faculty of Chemical Engineering Technology, Universiti Malaysia Perlis (UniMAP), Arau, Perlis, 02600, Malaysia
| | - Liang-Zhou Xu
- Department of Radiology, Wuhan Hospital Of Traditional Chinese Medicine, Wuhan, Hubei, China
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30
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Li J, Peng D, Xie Y, Dai Z, Zou X, Li Z. Novel Potential Small Molecule-MiRNA-Cancer Associations Prediction Model Based on Fingerprint, Sequence, and Clinical Symptoms. J Chem Inf Model 2021; 61:2208-2219. [PMID: 33899462 DOI: 10.1021/acs.jcim.0c01458] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
As an important biomarker in organisms, miRNA is closely related to various small molecules and diseases. Research on small molecule-miRNA-cancer associations is helpful for the development of cancer treatment drugs and the discovery of pathogenesis. It is very urgent to develop theoretical methods for identifying potential small molecular-miRNA-cancer associations, because experimental approaches are usually time-consuming, laborious, and expensive. To overcome this problem, we developed a new computational method, in which features derived from structure, sequence, and symptoms were utilized to characterize small molecule, miRNA, and cancer, respectively. A feature vector was construct to characterize small molecule-miRNA-cancer association by concatenating these features, and a random forest algorithm was utilized to construct a model for recognizing potential association. Based on the 5-fold cross-validation and benchmark data set, the model achieved an accuracy of 93.20 ± 0.52%, a precision of 93.22 ± 0.51%, a recall of 93.20 ± 0.53%, and an F1-measure of 93.20 ± 0.52%. The areas under the receiver operating characteristic curve and precision recall curve were 0.9873 and 0.9870. The real prediction ability and application performance of the developed method have also been further evaluated and verified through an independent data set test and case study. Some potential small molecules and miRNAs related to cancer have been identified and are worthy of further experimental research. It is anticipated that our model could be regarded as a useful high-throughput virtual screening tool for drug research and development. All source codes can be downloaded from https://github.com/LeeKamlong/Multi-class-SMMCA.
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Affiliation(s)
- Jinlong Li
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, People's Republic of China
| | - Dongdong Peng
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, People's Republic of China
| | - Yun Xie
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, People's Republic of China
| | - Zong Dai
- School of Biomedical Engineering, Sun Yat-Sen University, Guangzhou 510275, People's Republic of China
| | - Xiaoyong Zou
- School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, People's Republic of China
| | - Zhanchao Li
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, People's Republic of China
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of Traditional Chinese Medicine, Guangzhou 510006, People's Republic of China
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31
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Bood M, Del Nogal AW, Nilsson JR, Edfeldt F, Dahlén A, Lemurell M, Wilhelmsson LM, Grøtli M. Interbase-FRET binding assay for pre-microRNAs. Sci Rep 2021; 11:9396. [PMID: 33931703 PMCID: PMC8087795 DOI: 10.1038/s41598-021-88922-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023] Open
Abstract
The aberrant expression of microRNAs (miRs) has been linked to several human diseases. A promising approach for targeting these anomalies is the use of small-molecule inhibitors of miR biogenesis. These inhibitors have the potential to (i) dissect miR mechanisms of action, (ii) discover new drug targets, and (iii) function as new therapeutic agents. Here, we designed Förster resonance energy transfer (FRET)-labeled oligoribonucleotides of the precursor of the oncogenic miR-21 (pre-miR-21) and used them together with a set of aminoglycosides to develop an interbase-FRET assay to detect ligand binding to pre-miRs. Our interbase-FRET assay accurately reports structural changes of the RNA oligonucleotide induced by ligand binding. We demonstrate its application in a rapid, qualitative drug candidate screen by assessing the relative binding affinity between 12 aminoglycoside antibiotics and pre-miR-21. Surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) were used to validate our new FRET method, and the accuracy of our FRET assay was shown to be similar to the established techniques. With its advantages over SPR and ITC owing to its high sensitivity, small sample size, straightforward technique and the possibility for high-throughput expansion, we envision that our solution-based method can be applied in pre-miRNA–target binding studies.
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Affiliation(s)
- Mattias Bood
- Department of Chemistry and Molecular Biology, University of Gothenburg, 412 96, Gothenburg, Sweden.,Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden
| | - Anna Wypijewska Del Nogal
- Department of Chemistry and Chemical Engineering, Chemistry and Biochemistry, Chalmers University of Technology, 412 96, Gothenburg, Sweden
| | - Jesper R Nilsson
- Department of Chemistry and Chemical Engineering, Chemistry and Biochemistry, Chalmers University of Technology, 412 96, Gothenburg, Sweden
| | - Fredrik Edfeldt
- Structure & Biophysics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden
| | - Anders Dahlén
- Oligonucleotide Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden
| | - Malin Lemurell
- Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden
| | - L Marcus Wilhelmsson
- Department of Chemistry and Chemical Engineering, Chemistry and Biochemistry, Chalmers University of Technology, 412 96, Gothenburg, Sweden
| | - Morten Grøtli
- Department of Chemistry and Molecular Biology, University of Gothenburg, 412 96, Gothenburg, Sweden.
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32
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Noncoding RNAs in Glioblastoma: Emerging Biological Concepts and Potential Therapeutic Implications. Cancers (Basel) 2021; 13:cancers13071555. [PMID: 33800703 PMCID: PMC8037102 DOI: 10.3390/cancers13071555] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/28/2021] [Accepted: 03/19/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary Since the completion of the Human Genome Project, noncoding RNAs (ncRNAs) have emerged as an important class of genetic regulators. Several classes of ncRNAs, which include microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and piwi-interacting RNAs (piRNAs), have been shown to play important roles in controlling developmental and disease processes. In this article, we discuss the potential roles of ncRNAs in regulating glioblastoma (GBM) formation and progression as well as potential strategies to exploit the diagnostic and therapeutic potential of ncRNAs in GBM. Abstract Noncoding RNAs (ncRNAs) have emerged as a novel class of genomic regulators, ushering in a new era in molecular biology. With the advent of advanced genetic sequencing technology, several different classes of ncRNAs have been uncovered, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and piwi-interacting RNAs (piRNAs), which have been linked to many important developmental and disease processes and are being pursued as clinical and therapeutic targets. Molecular phenotyping studies of glioblastoma (GBM), the most common and lethal cancer of the adult brain, revealed that several ncRNAs are frequently dysregulated in its pathogenesis. Additionally, ncRNAs regulate many important aspects of glioma biology including tumour cell proliferation, migration, invasion, apoptosis, angiogenesis, and self-renewal. Here, we present an overview of the biogenesis of the different classes of ncRNAs, discuss their biological roles, as well as their relevance to gliomagenesis. We conclude by discussing potential approaches to therapeutically target the ncRNAs in clinic.
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33
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Liu D, Wan X, Shan X, Fan R, Zha W. Drugging the "undruggable" microRNAs. Cell Mol Life Sci 2021; 78:1861-1871. [PMID: 33052435 PMCID: PMC11073314 DOI: 10.1007/s00018-020-03676-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 09/07/2020] [Accepted: 10/05/2020] [Indexed: 12/14/2022]
Abstract
As a naturally occurring class of gene regulators, microRNAs (miRNAs) have attracted much attention as promising targets for therapeutic development. However, RNAs including miRNAs have long been considered undruggable, and most efforts have been devoted to using synthetic oligonucleotides to regulate miRNAs. Encouragingly, recent findings have revealed that miRNAs can also be drugged with small molecules that directly target miRNAs. In this review paper, we give a summary of recently emerged small-molecule inhibitors (SMIs) and small-molecule degraders (SMDs) for miRNAs. SMIs are small molecules that directly bind to miRNAs to inhibit their biogenesis, and SMDs are bifunctional small molecules that upon binding to miRNAs induce miRNA degradation. Strategies for discovering SMIs and developing SMDs were summarized. Applications of SMIs and SMDs in miRNA inhibition and cancer therapy were also introduced. Overall, SMIs and SMDs introduced here have high potency and specificity in miRNA inhibition. We envision that these small molecules will pave the way for developing novel therapeutics toward miRNAs that were previously considered undruggable.
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Affiliation(s)
- Dejun Liu
- The Yancheng Clinical College of Xuzhou Medical University, Yancheng, 224001, China
| | - Xinqiang Wan
- Department of Gynaecology and Obstetrics, Yancheng City No.1 People's Hospital, Yancheng, 224001, China
| | - Xiangxiang Shan
- Department of Geraeology, Yancheng City No.1 People's Hospital, Yancheng, 224001, China
| | - Rengen Fan
- Department of General Surgery, Yancheng City No.1 People's Hospital, Yancheng, 224001, China.
| | - Wenzhang Zha
- Department of General Surgery, Yancheng City No.1 People's Hospital, Yancheng, 224001, China.
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34
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Raue R, Frank AC, Syed SN, Brüne B. Therapeutic Targeting of MicroRNAs in the Tumor Microenvironment. Int J Mol Sci 2021; 22:ijms22042210. [PMID: 33672261 PMCID: PMC7926641 DOI: 10.3390/ijms22042210] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/16/2021] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
The tumor-microenvironment (TME) is an amalgamation of various factors derived from malignant cells and infiltrating host cells, including cells of the immune system. One of the important factors of the TME is microRNAs (miRs) that regulate target gene expression at a post transcriptional level. MiRs have been found to be dysregulated in tumor as well as in stromal cells and they emerged as important regulators of tumorigenesis. In fact, miRs regulate almost all hallmarks of cancer, thus making them attractive tools and targets for novel anti-tumoral treatment strategies. Tumor to stroma cell cross-propagation of miRs to regulate protumoral functions has been a salient feature of the TME. MiRs can either act as tumor suppressors or oncogenes (oncomiRs) and both miR mimics as well as miR inhibitors (antimiRs) have been used in preclinical trials to alter cancer and stromal cell phenotypes. Owing to their cascading ability to regulate upstream target genes and their chemical nature, which allows specific pharmacological targeting, miRs are attractive targets for anti-tumor therapy. In this review, we cover a recent update on our understanding of dysregulated miRs in the TME and provide an overview of how these miRs are involved in current cancer-therapeutic approaches from bench to bedside.
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Affiliation(s)
- Rebecca Raue
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.)
| | - Ann-Christin Frank
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.)
| | - Shahzad Nawaz Syed
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.)
- Correspondence: (S.N.S.); (B.B.); Tel.: +49-69-6301-7424 (B.B.)
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.)
- Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology, 60596 Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt, 60590 Frankfurt, Germany
- Frankfurt Cancer Institute, Goethe-University Frankfurt, 60596 Frankfurt, Germany
- Correspondence: (S.N.S.); (B.B.); Tel.: +49-69-6301-7424 (B.B.)
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35
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Shen C, Luo J, Ouyang W, Ding P, Wu H. Identification of Small Molecule–miRNA Associations with Graph Regularization Techniques in Heterogeneous Networks. J Chem Inf Model 2020; 60:6709-6721. [DOI: 10.1021/acs.jcim.0c00975] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- Cong Shen
- College of Computer Science and Electronic Engineering, Hunan University, Changsha 410083, China
| | - Jiawei Luo
- College of Computer Science and Electronic Engineering, Hunan University, Changsha 410083, China
| | - Wenjue Ouyang
- College of Computer Science and Electronic Engineering, Hunan University, Changsha 410083, China
| | - Pingjian Ding
- School of Computer Science, University of South China, Hengyang 421001, China
| | - Hao Wu
- College of Computer Science and Electronic Engineering, Hunan University, Changsha 410083, China
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36
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Xu P, Wu Q, Lu D, Yu J, Rao Y, Kou Z, Fang G, Liu W, Han H. A systematic study of critical miRNAs on cells proliferation and apoptosis by the shortest path. BMC Bioinformatics 2020; 21:396. [PMID: 32894041 PMCID: PMC7487489 DOI: 10.1186/s12859-020-03732-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 09/01/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND MicroRNAs are a class of important small noncoding RNAs, which have been reported to be involved in the processes of tumorigenesis and development by targeting a few genes. Existing studies show that the imbalance between cell proliferation and apoptosis is closely related to the initiation and development of cancers. However, the impact of miRNAs on this imbalance has not been studied systematically. RESULTS In this study, we first construct a cell fate miRNA-gene regulatory network. Then, we propose a systematical method for calculating the global impact of miRNAs on cell fate genes based on the shortest path. Results on breast cancer and liver cancer datasets show that most of the cell fate genes are perturbed by the differentially expressed miRNAs. Most of the top-identified miRNAs are verified in the Human MicroRNA Disease Database (HMDD) and are related to breast and liver cancers. Function analysis shows that the top 20 miRNAs regulate multiple cell fate related function modules and interact tightly based on their functional similarity. Furthermore, more than half of them can promote sensitivity or induce resistance to some anti-cancer drugs. Besides, survival analysis demonstrates that the top-ranked miRNAs are significantly related to the overall survival time in the breast and liver cancers group. CONCLUSION In sum, this study can help to systematically study the important role of miRNAs on proliferation and apoptosis and thereby uncover the key miRNAs during the process of tumorigenesis. Furthermore, the results of this study will contribute to the development of clinical therapy based miRNAs for cancers.
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Affiliation(s)
- Peng Xu
- Institute of computational science and technology, Guangzhou University, Guangzhou, 510006, Guangdong, China.,School of computer science of information technology, Qiannan Normal University for Nationalities, Duyun, 558000, Guizhou, China
| | - Qian Wu
- College of Computer Science and Artificial Intelligence, Wenzhou University, Wenzhou, 325035, China
| | - Deyang Lu
- Institute of computational science and technology, Guangzhou University, Guangzhou, 510006, Guangdong, China
| | - Jian Yu
- Institute of computational science and technology, Guangzhou University, Guangzhou, 510006, Guangdong, China
| | - Yongsheng Rao
- Institute of computational science and technology, Guangzhou University, Guangzhou, 510006, Guangdong, China
| | - Zheng Kou
- Institute of computational science and technology, Guangzhou University, Guangzhou, 510006, Guangdong, China
| | - Gang Fang
- Institute of computational science and technology, Guangzhou University, Guangzhou, 510006, Guangdong, China
| | - Wenbin Liu
- Institute of computational science and technology, Guangzhou University, Guangzhou, 510006, Guangdong, China.
| | - Henry Han
- Department of Computer and Information Science, Fordham University, New York, NY, 10023, USA.
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37
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Loibl N, Arenz C, Seitz O. Monitoring Dicer-Mediated miRNA-21 Maturation and Ago2 Loading by a Dual-Colour FIT PNA Probe Set. Chembiochem 2020; 21:2527-2532. [PMID: 32270536 PMCID: PMC7496889 DOI: 10.1002/cbic.202000173] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/06/2020] [Indexed: 12/14/2022]
Abstract
The inhibition of micro RNA (miRNA) maturation by Dicer and loading matured miRNAs into the RNA-induced silencing complex (RISC) is envisioned as a modality for treatment of cancer. Existing methods for evaluating maturation either focus on the conversion of modified precursors or detect mature miRNA. Whereas the former is not applicable to native pre-miRNA, the latter approach underestimates maturation when both nonmatured and matured miRNA molecules are subject to cleavage. We present a set of two orthogonally labelled FIT PNA probes that distinguish between cleaved pre-miRNA and the mature miRNA duplex. The probes allow Dicer-mediated miR21 maturation to be monitored and Ago2-mediated unwinding of the miR21 duplex to be assayed. A two-channel fluorescence readout enables measurement in real-time without the need for specialized instrumentation or further enzyme mediated amplification.
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Affiliation(s)
- Natalia Loibl
- Department of ChemistryHumbolt-Universität zu BerlinBrook-Taylor-Strase 212489BerlinGermany
| | - Christoph Arenz
- Department of ChemistryHumbolt-Universität zu BerlinBrook-Taylor-Strase 212489BerlinGermany
| | - Oliver Seitz
- Department of ChemistryHumbolt-Universität zu BerlinBrook-Taylor-Strase 212489BerlinGermany
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38
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Zhang B, Tian L, Xie J, Chen G, Wang F. Targeting miRNAs by natural products: A new way for cancer therapy. Biomed Pharmacother 2020; 130:110546. [PMID: 32721631 DOI: 10.1016/j.biopha.2020.110546] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 07/13/2020] [Accepted: 07/20/2020] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression through mRNA degradation or translation inhibition. MiRNAs play important roles in a variety of biological processes, and dysregulation of miRNA expression is highly associated with cancer development. Individual miRNA regulates multiple gene expressions, enabling them to regulate multiple cellular signaling pathways simultaneously. Hence, miRNAs could be served as cancer biomarkers for diagnosis and prognosis, and also therapeutic targets. Recently, more and more evidences showed that natural products such as paclitaxel, curcumin, resveratrol, genistein or epigallocatechin-3-gallate exert their anti-proliferative and/or pro-apoptotic effects through regulating one or more miRNAs, leading to the inhibition of cancer cell growth, induction of apoptosis or enhancement of conventional cancer therapeutic efficacy. Herein, we outlined the recent advances in the regulation of miRNAs expression by the natural products and highlight the importance of these natural drugs as a potential strategy in cancer treatment. This review will help us better understand how natural products modulate miRNAs and contribute to the development of effective and safe natural drugs for therapeutic purposes.
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Affiliation(s)
- Beilei Zhang
- Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710071, China; Department of Gynecology and Obstetrics, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710038, China
| | - Ling Tian
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, 510632, Guangzhou, Guangdong, China
| | - Jinrong Xie
- Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710071, China
| | - Guo Chen
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, 510632, Guangzhou, Guangdong, China.
| | - Fu Wang
- Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710071, China.
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39
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Shen C, Luo J, Lai Z, Ding P. Multiview Joint Learning-Based Method for Identifying Small-Molecule-Associated MiRNAs by Integrating Pharmacological, Genomics, and Network Knowledge. J Chem Inf Model 2020; 60:4085-4097. [DOI: 10.1021/acs.jcim.0c00244] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Cong Shen
- College of Computer Science and Electronic Engineering, Hunan University, Changsha 410083, China
| | - Jiawei Luo
- College of Computer Science and Electronic Engineering, Hunan University, Changsha 410083, China
| | - Zihan Lai
- College of Computer Science and Electronic Engineering, Hunan University, Changsha 410083, China
| | - Pingjian Ding
- School of Computer Science, University of South China, Hengyang 421001, China
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40
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RNA-Targeted Therapies and High-Throughput Screening Methods. Int J Mol Sci 2020; 21:ijms21082996. [PMID: 32340368 PMCID: PMC7216119 DOI: 10.3390/ijms21082996] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 02/07/2023] Open
Abstract
RNA-binding proteins (RBPs) are involved in regulating all aspects of RNA metabolism, including processing, transport, translation, and degradation. Dysregulation of RNA metabolism is linked to a plethora of diseases, such as cancer, neurodegenerative diseases, and neuromuscular disorders. Recent years have seen a dramatic shift in the knowledge base, with RNA increasingly being recognised as an attractive target for precision medicine therapies. In this article, we are going to review current RNA-targeted therapies. Furthermore, we will scrutinise a range of drug discoveries targeting protein-RNA interactions. In particular, we will focus on the interplay between Lin28 and let-7, splicing regulatory proteins and survival motor neuron (SMN) pre-mRNA, as well as HuR, Musashi, proteins and their RNA targets. We will highlight the mechanisms RBPs utilise to modulate RNA metabolism and discuss current high-throughput screening strategies. This review provides evidence that we are entering a new era of RNA-targeted medicine.
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41
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Van Meter EN, Onyango JA, Teske KA. A review of currently identified small molecule modulators of microRNA function. Eur J Med Chem 2020; 188:112008. [DOI: 10.1016/j.ejmech.2019.112008] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 12/06/2019] [Accepted: 12/20/2019] [Indexed: 12/13/2022]
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42
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Wang CC, Chen X. A Unified Framework for the Prediction of Small Molecule–MicroRNA Association Based on Cross-Layer Dependency Inference on Multilayered Networks. J Chem Inf Model 2019; 59:5281-5293. [DOI: 10.1021/acs.jcim.9b00667] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Chun-Chun Wang
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou 221116, China
| | - Xing Chen
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou 221116, China
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43
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Murata A, Nakamori M, Nakatani K. Modulating RNA secondary and tertiary structures by mismatch binding ligands. Methods 2019; 167:78-91. [DOI: 10.1016/j.ymeth.2019.05.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 05/05/2019] [Accepted: 05/07/2019] [Indexed: 12/21/2022] Open
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44
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Hei YY, Guo YX, Jiang CS, Wang S, Lu SM, Zhang SQ. The dual luciferase reporter system and RT-qPCR strategies for screening of MicroRNA-21 small-molecule inhibitors. Biotechnol Appl Biochem 2019; 66:755-762. [PMID: 31021480 DOI: 10.1002/bab.1756] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 04/15/2019] [Indexed: 12/12/2022]
Abstract
The therapeutic potential of microRNA-21 (miR-21) small-molecule inhibitors has been of particular interest to medicinal chemists. Moreover, the development of more facile screening methods is lacking. In the present study, two potential screening strategies for miR-21 small-molecule inhibitor including the stem-loop reverse transcription-quantitative PCR and dual luciferase reporter assay system were demonstrated and discussed in detail. A pmirGLO-miR21cswt plasmid and its two different mutants were constructed for dual luciferase reporter assay system. In addition, the sensitivity and specificity of these two methods were validated. Our results demonstrated that both strategies are decent choices for the screening of small-molecule inhibitors for miR-21 and possibly other miRNAs. Eventually, we applied our optimized strategy to discover and characterize several promising compounds such as azobenzene derivate A, enoxacin, and norfloxacin for their potential impact on intracellular miR-21 concentration.
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Affiliation(s)
- Yuan-Yuan Hei
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
| | - Yuan-Xu Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, People's Republic of China
| | - Cong-Shan Jiang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, People's Republic of China
| | - Si Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, People's Republic of China
| | - She-Min Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, People's Republic of China
| | - San-Qi Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
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45
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Ankenbruck N, Kumbhare R, Naro Y, Thomas M, Gardner L, Emanuelson C, Deiters A. Small molecule inhibition of microRNA-21 expression reduces cell viability and microtumor formation. Bioorg Med Chem 2019; 27:3735-3743. [DOI: 10.1016/j.bmc.2019.05.044] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 05/01/2019] [Accepted: 05/28/2019] [Indexed: 12/21/2022]
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46
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Abstract
RNA structures play a pivotal role in many biological processes and the progression of human disease, making them an attractive target for therapeutic development. Often RNA structures operate through the formation of complexes with RNA-binding proteins, however, much like protein-protein interactions, RNA-protein interactions span large surface areas and often lack traditional druggable properties, making it challenging to target them with small molecules. Peptides provide much greater surface areas and therefore greater potential for forming specific and high affinity interactions with RNA. In this chapter, we discuss our approach for engineering peptides that bind to structured RNAs by highlighting methods and design strategies from previous successful projects aimed at inhibiting the HIV Tat-TAR interaction and the biogenesis of oncogenic microRNAs.
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Affiliation(s)
- Matthew J Walker
- Department of Chemistry, University of Washington, Seattle, WA, United States
| | - Gabriele Varani
- Department of Chemistry, University of Washington, Seattle, WA, United States.
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47
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Yan H, Liang FS. miRNA inhibition by proximity-enabled Dicer inactivation. Methods 2019; 167:117-123. [PMID: 31077820 DOI: 10.1016/j.ymeth.2019.05.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 04/22/2019] [Accepted: 05/05/2019] [Indexed: 11/17/2022] Open
Abstract
microRNAs (miRNAs) are considered as master regulators of biological processes. Dysregulation of miRNA expression has been implicated in many human diseases. Driven by the key biological roles and the therapeutic potential, developing methods for miRNA regulation has become an intense research area. Due to favorable pharmacological properties, small molecule-based miRNA inhibition emerges as a promising strategy and significant progresses have been made. However, it remains challenging to regulate miRNA using small molecules because of the inherent difficulty in RNA targeting and inhibition. Herein we outline the workflow of generating bifunctional small molecule inhibitors blocking miRNA biogenesis through proximity-enabled inactivation of Dicer, an enzyme required for the processing of precursor miRNA (pre-miRNA) into mature miRNA. By conjugating a weak Dicer inhibitor with a pre-miRNA binder, the inhibitor can be delivered to the Dicer processing site associated with the targeted pre-miRNA, and as a result inhibiting Dicer-mediated pre-miRNA processing. This protocol can be applicable in producing bifunctional inhibitors for different miRNAs.
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Affiliation(s)
- Hao Yan
- Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, United States
| | - Fu-Sen Liang
- Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, United States.
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48
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Garner AL, Lorenz DA, Sandoval J, Gallagher EE, Kerk SA, Kaur T, Menon A. Tetracyclines as Inhibitors of Pre-microRNA Maturation: A Disconnection between RNA Binding and Inhibition. ACS Med Chem Lett 2019; 10:816-821. [PMID: 31098005 DOI: 10.1021/acsmedchemlett.9b00091] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 04/22/2019] [Indexed: 12/21/2022] Open
Abstract
In a high-throughput screening campaign, we recently discovered the rRNA-binding tetracyclines, methacycline and meclocycline, as inhibitors of Dicer-mediated processing of microRNAs. Herein, we describe our biophysical and biochemical characterization of these compounds. Interestingly, although direct, albeit weak, binding to the pre-microRNA hairpins was observed, the inhibitory activity of these compounds was not due to RNA binding. Through additional biochemical and chemical studies, we revealed that metal chelation likely plays a principle role in their mechanism of inhibition. By exploring the activity of other known RNA-binding scaffolds, we identified additional disconnections between direct RNA interaction and inhibition of Dicer processing. Thus, the results presented within provide a valuable case study in the complexities of targeting RNA with small molecules, particularly with weak binding and potentially promiscuous scaffolds.
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49
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Otabe T, Nagano K, Kawai G, Murata A, Nakatani K. Inhibition of pre-miRNA-136 processing by Dicer with small molecule BzDANP suggested the formation of ternary complex of pre-miR-136–BzDANP–Dicer. Bioorg Med Chem 2019; 27:2140-2148. [DOI: 10.1016/j.bmc.2019.03.031] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 03/04/2019] [Accepted: 03/16/2019] [Indexed: 11/27/2022]
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50
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Fan R, Xiao C, Wan X, Cha W, Miao Y, Zhou Y, Qin C, Cui T, Su F, Shan X. Small molecules with big roles in microRNA chemical biology and microRNA-targeted therapeutics. RNA Biol 2019; 16:707-718. [PMID: 30900502 DOI: 10.1080/15476286.2019.1593094] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression. Aberrant miRNA expression or function have close links with various human diseases. Therefore, therapeutic treatments with disease-associated miRNAs as targets are emerging. However, the intracellular miRNA networks are extremely complicated and poorly understood, which thus hinder the development of miRNA-targeted therapeutics. Small molecules that are able to regulate endogenous miRNAs hold great potential in both elucidation of miRNA networks and treatment of miRNA-related diseases. Herein, we summarize current strategies for discovery of small molecule modifiers of miRNAs, and we highlight aspects of miRNA cellular biology elucidated by using these small molecules and miRNA-targeted therapeutics realized by these small molecules. We envision that this area will expand dramatically in the near future and will ultimately contribute to a better understanding of miRNA-involved cellular processes and development of therapeutic agents for miRNA-associated diseases.
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Affiliation(s)
- Rengen Fan
- a Department of General Surgery, Yancheng City No. 1 People's Hospital , Yancheng , China
| | - Chaocheng Xiao
- b Department of General Surgery, Yancheng City No. 1 People's Hospital , Yancheng , China
| | - Xinqiang Wan
- c Department of Gynaecology and Obstetrics, Yancheng City No. 1 People's Hospital , Yancheng , China
| | - Wenzhang Cha
- a Department of General Surgery, Yancheng City No. 1 People's Hospital , Yancheng , China
| | - Yufeng Miao
- d Department of Medical Oncology , Wuxi Third People's Hospital , Wuxi , China
| | - Yong Zhou
- a Department of General Surgery, Yancheng City No. 1 People's Hospital , Yancheng , China
| | - Chenglin Qin
- a Department of General Surgery, Yancheng City No. 1 People's Hospital , Yancheng , China
| | - Ting Cui
- e Department of Cardiology, The Third People's Hospital of Yancheng , Yancheng , China
| | - Fenglian Su
- f School of Medical University, Xuzhou , Xuzhou , China
| | - Xiangxiang Shan
- g Department of Geraeology, Yancheng City No.1 People's Hospital , Yancheng , China
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