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Xie S, Cao S, Wu J, Xie Z, Liu YT, Fu W, Zhao Q, Liu L, Yang L, Li J. In silico-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1. J Biomol Struct Dyn 2024; 42:5229-5237. [PMID: 37349935 DOI: 10.1080/07391102.2023.2226745] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 06/09/2023] [Indexed: 06/24/2023]
Abstract
The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has led to over 600 million cases of coronavirus disease 2019 (COVID-19). Identifying effective molecules that can counteract the virus is imperative. SARS-CoV-2 macrodomain 1 (Mac1) represents a promising antiviral drug target. In this study, we predicted potential inhibitors of SARS-CoV-2 Mac1 from natural products using in silico-based screening. Based on the high-resolution crystal structure of Mac1 bound to its endogenous ligand ADP-ribose (ADPr), we first performed a docking-based virtual screening of Mac1 inhibitors against a natural product library and obtained five representative compounds (MC1-MC5) by clustering analysis. All five compounds were stably bound to Mac1 during 500 ns long molecular dynamics simulations. The binding free energy of these compounds to Mac1 was calculated using molecular mechanics generalized Born surface area and further refined with localized volume-based metadynamics. The results demonstrated that both MC1 (-9.8 ± 0.3 kcal/mol) and MC5 (-9.6 ± 0.3 kcal/mol) displayed more favorable affinities to Mac1 with respect to ADPr (-8.9 ± 0.3 kcal/mol), highlighting their potential as potent SARS-CoV-2 Mac1 inhibitors. Overall, this study provides potential SARS-CoV-2 Mac1 inhibitors, which may pave the way for developing effective therapeutics for COVID-19.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Song Xie
- College of Chemistry, Fuzhou University, Fuzhou, China
| | - Shoujing Cao
- College of Chemistry, Fuzhou University, Fuzhou, China
| | - Juhong Wu
- College of Chemistry, Fuzhou University, Fuzhou, China
| | - Zhinuo Xie
- College of Chemistry, Fuzhou University, Fuzhou, China
| | | | - Wei Fu
- College of Chemistry, Fuzhou University, Fuzhou, China
| | - Qianqian Zhao
- College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Lin Liu
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Lin Yang
- Department of Pharmacy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Jinyu Li
- College of Chemistry, Fuzhou University, Fuzhou, China
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2
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Orosz L, Sárvári KP, Dernovics Á, Rosztóczy A, Megyeri K. Pathogenesis and clinical features of severe hepatitis E virus infection. World J Virol 2024; 13:91580. [PMID: 38984076 PMCID: PMC11229844 DOI: 10.5501/wjv.v13.i2.91580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/08/2024] [Accepted: 04/15/2024] [Indexed: 06/24/2024] Open
Abstract
The hepatitis E virus (HEV), a member of the Hepeviridae family, is a small, non-enveloped icosahedral virus divided into eight distinct genotypes (HEV-1 to HEV-8). Only genotypes 1 to 4 are known to cause diseases in humans. Genotypes 1 and 2 commonly spread via fecal-oral transmission, often through the consumption of contaminated water. Genotypes 3 and 4 are known to infect pigs, deer, and wild boars, often transferring to humans through inadequately cooked meat. Acute hepatitis caused by HEV in healthy individuals is mostly asymptomatic or associated with minor symptoms, such as jaundice. However, in immunosuppressed individuals, the disease can progress to chronic hepatitis and even escalate to cirrhosis. For pregnant women, an HEV infection can cause fulminant liver failure, with a potential mortality rate of 25%. Mortality rates also rise amongst cirrhotic patients when they contract an acute HEV infection, which can even trigger acute-on-chronic liver failure if layered onto pre-existing chronic liver disease. As the prevalence of HEV infection continues to rise worldwide, highlighting the particular risks associated with severe HEV infection is of major medical interest. This text offers a brief summary of the characteristics of hepatitis developed by patient groups at an elevated risk of severe HEV infection.
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Affiliation(s)
- László Orosz
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Károly Péter Sárvári
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Áron Dernovics
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - András Rosztóczy
- Department of Internal Medicine, Division of Gastroenterology, University of Szeged, Szeged 6725, Csongrád-Csanád, Hungary
| | - Klára Megyeri
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
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Wazir S, Parviainen TAO, Pfannenstiel JJ, Duong MTH, Cluff D, Sowa ST, Galera-Prat A, Ferraris D, Maksimainen MM, Fehr AR, Heiskanen JP, Lehtiö L. Discovery of 2-Amide-3-methylester Thiophenes that Target SARS-CoV-2 Mac1 and Repress Coronavirus Replication, Validating Mac1 as an Antiviral Target. J Med Chem 2024; 67:6519-6536. [PMID: 38592023 PMCID: PMC11144470 DOI: 10.1021/acs.jmedchem.3c02451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2024]
Abstract
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed. Here, we describe small-molecule inhibitors for SARS-CoV-2 Mac1, which counters ADP-ribosylation-mediated innate immune responses. Three high-throughput screening hits had the same 2-amide-3-methylester thiophene scaffold. We studied the compound binding mode using X-ray crystallography, allowing us to design analogues. Compound 27 (MDOLL-0229) had an IC50 of 2.1 μM and was selective for CoV Mac1 proteins after profiling for activity against a panel of viral and human proteins. The improved potency allowed testing of its effect on virus replication, and indeed, 27 inhibited replication of both murine hepatitis virus (MHV) prototypes CoV and SARS-CoV-2. Sequencing of a drug-resistant MHV identified mutations in Mac1, further demonstrating the specificity of 27. Compound 27 is the first Mac1-targeted small molecule demonstrated to inhibit coronavirus replication in a cell model.
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Affiliation(s)
- Sarah Wazir
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, 90220 Oulu, Finland
| | - Tomi A. O. Parviainen
- Research Unit of Sustainable Chemistry, University of Oulu, P.O. Box 4300, 90014 Oulu, Finland
| | - Jessica J. Pfannenstiel
- Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045, United States of America
| | - Men Thi Hoai Duong
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, 90220 Oulu, Finland
| | - Daniel Cluff
- Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045, United States of America
| | - Sven T. Sowa
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, 90220 Oulu, Finland
| | - Albert Galera-Prat
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, 90220 Oulu, Finland
| | - Dana Ferraris
- McDaniel College Department of Chemistry, 2 College Hill, Westminster, MD 21157, USA
| | - Mirko M. Maksimainen
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, 90220 Oulu, Finland
| | - Anthony R. Fehr
- Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045, United States of America
| | - Juha P. Heiskanen
- Research Unit of Sustainable Chemistry, University of Oulu, P.O. Box 4300, 90014 Oulu, Finland
| | - Lari Lehtiö
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, 90220 Oulu, Finland
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Li X, Song Y. Targeting SARS-CoV-2 nonstructural protein 3: Function, structure, inhibition, and perspective in drug discovery. Drug Discov Today 2024; 29:103832. [PMID: 37977285 PMCID: PMC10872262 DOI: 10.1016/j.drudis.2023.103832] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/06/2023] [Accepted: 11/13/2023] [Indexed: 11/19/2023]
Abstract
As a highly contagious human pathogen, severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) has infected billions of people worldwide with more than 6 million deaths. With several effective vaccines and antiviral drugs now available, the SARS-CoV-2 pandemic been brought under control. However, a new pathogenic coronavirus could emerge in the future, given the zoonotic nature of this virus. Natural evolution and drug-induced mutations of SARS-CoV-2 also require continued efforts for new anti-coronavirus drugs. Nonstructural protein (nsp) 3 of CoVs is a large, multifunctional protein, containing a papain-like protease (PLpro) and a macrodomain (Mac1), which are essential for viral replication. Here, we provide a comprehensive review of the function, structure, and inhibition of SARS-CoV/-CoV-2 PLpro and Mac1. We also discuss advances in, and challenges to, the discovery of drugs against these targets.
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Affiliation(s)
- Xin Li
- Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
| | - Yongcheng Song
- Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
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Wazir S, Parviainen TAO, Pfannenstiel JJ, Duong MTH, Cluff D, Sowa ST, Galera-Prat A, Ferraris D, Maksimainen MM, Fehr AR, Heiskanen JP, Lehtiö L. Discovery of 2-amide-3-methylester thiophenes that target SARS-CoV-2 Mac1 and repress coronavirus replication, validating Mac1 as an anti-viral target. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.28.555062. [PMID: 38234730 PMCID: PMC10793406 DOI: 10.1101/2023.08.28.555062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2024]
Abstract
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed to combat additional SARS-CoV-2 variants or novel CoVs. Here, we describe small molecule inhibitors for SARS-CoV-2 Mac1, which counters ADP-ribosylation mediated innate immune responses. The compounds inhibiting Mac1 were discovered through high-throughput screening (HTS) using a protein FRET-based competition assay and the best hit compound had an IC50 of 14 μM. Three validated HTS hits have the same 2-amide-3-methylester thiophene scaffold and the scaffold was selected for structure-activity relationship (SAR) studies through commercial and synthesized analogs. We studied the compound binding mode in detail using X-ray crystallography and this allowed us to focus on specific features of the compound and design analogs. Compound 27 (MDOLL-0229) had an IC50 of 2.1 μM and was generally selective for CoV Mac1 proteins after profiling for activity against a panel of viral and human ADP-ribose binding proteins. The improved potency allowed testing of its effect on virus replication and indeed, 27 inhibited replication of both MHVa prototype CoV, and SARS-CoV-2. Furthermore, sequencing of a drug-resistant MHV identified mutations in Mac1, further demonstrating the specificity of 27. Compound 27 is the first Mac1 targeted small molecule demonstrated to inhibit coronavirus replication in a cell model. This, together with its well-defined binding mode, makes 27 a good candidate for further hit/lead-optimization efforts.
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Affiliation(s)
- Sarah Wazir
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Finland
| | - Tomi A. O. Parviainen
- Research Unit of Sustainable Chemistry, University of Oulu, P.O. Box 4300, FI-90014 Oulu, Finland
| | - Jessica J. Pfannenstiel
- Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, United States of America
| | - Men Thi Hoai Duong
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Finland
| | - Daniel Cluff
- Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, United States of America
| | - Sven T. Sowa
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Finland
| | - Albert Galera-Prat
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Finland
| | - Dana Ferraris
- McDaniel College Department of Chemistry, 2 College Hill, Westminster, MD, USA
| | - Mirko M. Maksimainen
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Finland
| | - Anthony R. Fehr
- Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, United States of America
| | - Juha P. Heiskanen
- Research Unit of Sustainable Chemistry, University of Oulu, P.O. Box 4300, FI-90014 Oulu, Finland
| | - Lari Lehtiö
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Finland
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6
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Politi MD, Gallo A, Bouras G, Birkou M, Canard B, Coutard B, Spyroulias GA. 1H, 13C, 15N backbone resonance assignment of apo and ADP-ribose bound forms of the macro domain of Hepatitis E virus through solution NMR spectroscopy. BIOMOLECULAR NMR ASSIGNMENTS 2023; 17:1-8. [PMID: 36272047 PMCID: PMC9589693 DOI: 10.1007/s12104-022-10111-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 09/28/2022] [Indexed: 06/02/2023]
Abstract
The genome of Hepatitis E virus (HEV) is 7.2 kilobases long and has three open reading frames. The largest one is ORF1, encoding a non-structural protein involved in the replication process, and whose processing is ill-defined. The ORF1 protein is a multi-modular protein which includes a macro domain (MD). MDs are evolutionarily conserved structures throughout all kingdoms of life. MDs participate in the recognition and removal of ADP-ribosylation, and specifically viral MDs have been identified as erasers of ADP-ribose moieties interpreting them as important players at escaping the early stages of host-immune response. A detailed structural analysis of the apo and bound to ADP-ribose state of the native HEV MD would provide the structural information to understand how HEV MD is implicated in virus-host interplay and how it interacts with its intracellular partner during viral replication. In the present study we present the high yield expression of the native macro domain of HEV and its analysis by solution NMR spectroscopy. The HEV MD is folded in solution and we present a nearly complete backbone and sidechains assignment for apo and bound states. In addition, a secondary structure prediction by TALOS + analysis was performed. The results indicated that HEV MD has a α/β/α topology very similar to that of most viral macro domains.
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Affiliation(s)
- Maria D Politi
- Department of Pharmacy, University of Patras, 26504, Patras, Greece
| | - Angelo Gallo
- Department of Chemistry, University of Torino, 10126, Torino, Italy
| | - Georgios Bouras
- Department of Pharmacy, University of Patras, 26504, Patras, Greece
| | - Maria Birkou
- Department of Pharmacy, University of Patras, 26504, Patras, Greece
| | - Bruno Canard
- Université Aix-Marseille, Architecture et Fonction des Macromolécules Biologiques (AFMB) - UMR7257 CNRS - Case 932, 163 avenue de Luminy, 13288, Marseille CEDEX 09, France
| | - Bruno Coutard
- Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207), Marseille, France.
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7
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ADP-Ribosylation in Antiviral Innate Immune Response. Pathogens 2023; 12:pathogens12020303. [PMID: 36839575 PMCID: PMC9964302 DOI: 10.3390/pathogens12020303] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023] Open
Abstract
Adenosine diphosphate (ADP)-ribosylation is a reversible post-translational modification catalyzed by ADP-ribosyltransferases (ARTs). ARTs transfer one or more ADP-ribose from nicotinamide adenine dinucleotide (NAD+) to the target substrate and release the nicotinamide (Nam). Accordingly, it comes in two forms: mono-ADP-ribosylation (MARylation) and poly-ADP-ribosylation (PARylation). ADP-ribosylation plays important roles in many biological processes, such as DNA damage repair, gene regulation, and energy metabolism. Emerging evidence demonstrates that ADP-ribosylation is implicated in host antiviral immune activity. Here, we summarize and discuss ADP-ribosylation modifications that occur on both host and viral proteins and their roles in host antiviral response.
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8
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Rack JGM, Ahel I. A Simple Method to Study ADP-Ribosylation Reversal: From Function to Drug Discovery. Methods Mol Biol 2023; 2609:111-132. [PMID: 36515833 DOI: 10.1007/978-1-0716-2891-1_8] [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] [Indexed: 12/15/2022]
Abstract
ADP-ribosylation is an ancient modification of proteins, nucleic acids, and other biomolecules found in all kingdoms of life as well as in certain viruses. The regulation of fundamental (patho)physiological processes by ADP-ribosylation, including the cellular stress response, inflammation, and immune response to bacterial and viral pathogens, has created a strong interest into the study of modification establishment and removal to explore novel therapeutic approaches. Beyond ADP-ribosylation in humans, direct targeting of factors that alter host ADP-ribosylation signaling (e.g., viral macrodomains) or utilize ADP-ribosylation to manipulate host cell behavior (e.g., bacterial toxins) were shown to reduce virulence and disease severity. However, the realization of these therapeutic potentials is thus far hampered by the unavailability of simple, high-throughput methods to study the modification "writers" and "erasers" and screen for novel inhibitors.Here, we describe a scalable method for the measurement of (ADP-ribosyl)hydrolase activity. The assay relies on the conversion of ADP-ribose released from a modified substrate by the (ADP-ribosyl)hydrolase under investigation into AMP by the phosphodiesterase NudT5 into bioluminescence via a commercially available detection assay. Moreover, this method can be utilized to study the role of nudix- or ENPP-type phosphodiesterases in ADP-ribosylation processing and may also be adapted to investigate the activity of (ADP-ribosyl)transferases. Overall, this method is applicable for both basic biochemical characterization and screening of large drug libraries; hence, it is highly adaptable to diverse project needs.
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Affiliation(s)
| | - Ivan Ahel
- Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
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9
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Gahbauer S, Correy GJ, Schuller M, Ferla MP, Doruk YU, Rachman M, Wu T, Diolaiti M, Wang S, Neitz RJ, Fearon D, Radchenko D, Moroz Y, Irwin JJ, Renslo AR, Taylor JC, Gestwicki JE, von Delft F, Ashworth A, Ahel I, Shoichet BK, Fraser JS. Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 Macrodomain of SARS-CoV-2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2022:2022.06.27.497816. [PMID: 35794891 PMCID: PMC9258288 DOI: 10.1101/2022.06.27.497816] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 152 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated protein dynamics within the active site, and key inhibitor motifs that will template future drug development against Mac1.
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Affiliation(s)
- Stefan Gahbauer
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
| | - Galen J. Correy
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA
| | - Marion Schuller
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
| | - Matteo P. Ferla
- Wellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK
- National Institute for Health Research Oxford Biomedical Research Centre, Oxford, OX4 2PG, UK
| | - Yagmur Umay Doruk
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Moira Rachman
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
| | - Taiasean Wu
- Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA 94158, USA
- Chemistry and Chemical Biology Graduate Program, University of California San Francisco, San Francisco, CA 94158, USA
| | - Morgan Diolaiti
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Siyi Wang
- Chemistry and Chemical Biology Graduate Program, University of California San Francisco, San Francisco, CA 94158, USA
| | - R. Jeffrey Neitz
- Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, California 94158, USA
| | - Daren Fearon
- Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK
- Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK
| | - Dmytro Radchenko
- Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine
- Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv, 01601, Ukraine
| | - Yurii Moroz
- Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv, 01601, Ukraine
- Chemspace, Chervonotkatska Street 78, Kyiv, 02094, Ukraine
| | - John J. Irwin
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
| | - Adam R. Renslo
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, California 94158, USA
| | - Jenny C. Taylor
- Wellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK
- National Institute for Health Research Oxford Biomedical Research Centre, Oxford, OX4 2PG, UK
| | - Jason E. Gestwicki
- Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA 94158, USA
- Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, California 94158, USA
| | - Frank von Delft
- Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK
- Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK
- Centre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK
- Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, UK
- Department of Biochemistry, University of Johannesburg, Auckland Park 2006, South Africa
| | - Alan Ashworth
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Ivan Ahel
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
| | - Brian K. Shoichet
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
| | - James S. Fraser
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA
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10
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Nizi M, Maksimainen MM, Lehtiö L, Tabarrini O. Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules. J Med Chem 2022; 65:7532-7560. [PMID: 35608571 PMCID: PMC9189837 DOI: 10.1021/acs.jmedchem.2c00281] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Indexed: 12/13/2022]
Abstract
Major advances have recently defined functions for human mono-ADP-ribosylating PARP enzymes (mono-ARTs), also opening up potential applications for targeting them to treat diseases. Structural biology combined with medicinal chemistry has allowed the design of potent small molecule inhibitors which typically bind to the catalytic domain. Most of these inhibitors are at the early stages, but some have already a suitable profile to be used as chemical tools. One compound targeting PARP7 has even progressed to clinical trials. In this review, we collect inhibitors of mono-ARTs with a typical "H-Y-Φ" motif (Φ = hydrophobic residue) and focus on compounds that have been reported as active against one or a restricted number of enzymes. We discuss them from a medicinal chemistry point of view and include an analysis of the available crystal structures, allowing us to craft a pharmacophore model that lays the foundation for obtaining new potent and more specific inhibitors.
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Affiliation(s)
- Maria
Giulia Nizi
- Department
of Pharmaceutical Sciences, University of
Perugia, 06123 Perugia, Italy
| | - Mirko M. Maksimainen
- Faculty
of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, 5400 Oulu, Finland
| | - Lari Lehtiö
- Faculty
of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, 5400 Oulu, Finland
| | - Oriana Tabarrini
- Department
of Pharmaceutical Sciences, University of
Perugia, 06123 Perugia, Italy
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11
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Lüscher B, Verheirstraeten M, Krieg S, Korn P. Intracellular mono-ADP-ribosyltransferases at the host-virus interphase. Cell Mol Life Sci 2022; 79:288. [PMID: 35536484 PMCID: PMC9087173 DOI: 10.1007/s00018-022-04290-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/15/2022] [Accepted: 04/05/2022] [Indexed: 01/22/2023]
Abstract
The innate immune system, the primary defense mechanism of higher organisms against pathogens including viruses, senses pathogen-associated molecular patterns (PAMPs). In response to PAMPs, interferons (IFNs) are produced, allowing the host to react swiftly to viral infection. In turn the expression of IFN-stimulated genes (ISGs) is induced. Their products disseminate the antiviral response. Among the ISGs conserved in many species are those encoding mono-ADP-ribosyltransferases (mono-ARTs). This prompts the question whether, and if so how, mono-ADP-ribosylation affects viral propagation. Emerging evidence demonstrates that some mono-ADP-ribosyltransferases function as PAMP receptors and modify both host and viral proteins relevant for viral replication. Support for mono-ADP-ribosylation in virus–host interaction stems from the findings that some viruses encode mono-ADP-ribosylhydrolases, which antagonize cellular mono-ARTs. We summarize and discuss the evidence linking mono-ADP-ribosylation and the enzymes relevant to catalyze this reversible modification with the innate immune response as part of the arms race between host and viruses.
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Affiliation(s)
- Bernhard Lüscher
- Institute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.
| | - Maud Verheirstraeten
- Institute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Sarah Krieg
- Institute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Patricia Korn
- Institute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.
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12
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Manco G, Lacerra G, Porzio E, Catara G. ADP-Ribosylation Post-Translational Modification: An Overview with a Focus on RNA Biology and New Pharmacological Perspectives. Biomolecules 2022; 12:biom12030443. [PMID: 35327636 PMCID: PMC8946771 DOI: 10.3390/biom12030443] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/02/2022] [Accepted: 03/10/2022] [Indexed: 02/04/2023] Open
Abstract
Cellular functions are regulated through the gene expression program by the transcription of new messenger RNAs (mRNAs), alternative RNA splicing, and protein synthesis. To this end, the post-translational modifications (PTMs) of proteins add another layer of complexity, creating a continuously fine-tuned regulatory network. ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules, regulating a multitude of key functional processes as diverse as DNA damage repair (DDR), transcriptional regulation, intracellular transport, immune and stress responses, and cell survival. Additionally, due to the emerging role of ADP-ribosylation in pathological processes, ADP-ribosyltransferases (ARTs), the enzymes involved in ADPr, are attracting growing interest as new drug targets. In this review, an overview of human ARTs and their related biological functions is provided, mainly focusing on the regulation of ADP-ribosyltransferase Diphtheria toxin-like enzymes (ARTD)-dependent RNA functions. Finally, in order to unravel novel gene functional relationships, we propose the analysis of an inventory of human gene clusters, including ARTDs, which share conserved sequences at 3′ untranslated regions (UTRs).
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Affiliation(s)
- Giuseppe Manco
- Institute of Biochemistry and Cell Biology, National Research Council of Italy, Via P. Castellino 111, 80131 Naples, Italy;
- Correspondence: (G.M.); (G.C.)
| | - Giuseppina Lacerra
- Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, National Research Council of Italy, Via P. Castellino 111, 80131 Naples, Italy;
| | - Elena Porzio
- Institute of Biochemistry and Cell Biology, National Research Council of Italy, Via P. Castellino 111, 80131 Naples, Italy;
| | - Giuliana Catara
- Institute of Biochemistry and Cell Biology, National Research Council of Italy, Via P. Castellino 111, 80131 Naples, Italy;
- Correspondence: (G.M.); (G.C.)
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13
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Unconventional metabolites in chromatin regulation. Biosci Rep 2022; 42:230604. [PMID: 34988581 PMCID: PMC8777195 DOI: 10.1042/bsr20211558] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 01/04/2022] [Accepted: 01/04/2022] [Indexed: 11/17/2022] Open
Abstract
Chromatin, the complex of DNA and histone proteins, serves as a main integrator of cellular signals. Increasing evidence links cellular functional to chromatin state. Indeed, different metabolites are emerging as modulators of chromatin function and structure. Alterations in chromatin state are decisive for regulating all aspects of genome function and ultimately have the potential to produce phenotypic changes. Several metabolites such as acetyl-CoA, S-adenosylmethionine (SAM) or adenosine triphosphate (ATP) have now been well characterized as main substrates or cofactors of chromatin-modifying enzymes. However, there are other metabolites that can directly interact with chromatin influencing its state or that modulate the properties of chromatin regulatory factors. Also, there is a growing list of atypical enzymatic and nonenzymatic chromatin modifications that originate from different cellular pathways that have not been in the limelight of chromatin research. Here, we summarize different properties and functions of uncommon regulatory molecules originating from intermediate metabolism of lipids, carbohydrates and amino acids. Based on the various modes of action on chromatin and the plethora of putative, so far not described chromatin-regulating metabolites, we propose that there are more links between cellular functional state and chromatin regulation to be discovered. We hypothesize that these connections could provide interesting starting points for interfering with cellular epigenetic states at a molecular level.
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