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1
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Pauly I, Kumar Singh A, Kumar A, Singh Y, Thareja S, Kamal MA, Verma A, Kumar P. Current Insights and Molecular Docking Studies of the Drugs under Clinical Trial as RdRp Inhibitors in COVID-19 Treatment. Curr Pharm Des 2023; 28:3677-3705. [PMID: 36345244 DOI: 10.2174/1381612829666221107123841] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 09/08/2022] [Accepted: 09/19/2022] [Indexed: 11/10/2022]
Abstract
Study Background & Objective: After the influenza pandemic (1918), COVID-19 was declared a Vth pandemic by the WHO in 2020. SARS-CoV-2 is an RNA-enveloped single-stranded virus. Based on the structure and life cycle, Protease (3CLpro), RdRp, ACE2, IL-6, and TMPRSS2 are the major targets for drug development against COVID-19. Pre-existing several drugs (FDA-approved) are used to inhibit the above targets in different diseases. In coronavirus treatment, these drugs are also in different clinical trial stages. Remdesivir (RdRp inhibitor) is the only FDA-approved medicine for coronavirus treatment. In the present study, by using the drug repurposing strategy, 70 preexisting clinical or under clinical trial molecules were used in scrutiny for RdRp inhibitor potent molecules in coronavirus treatment being surveyed via docking studies. Molecular simulation studies further confirmed the binding mechanism and stability of the most potent compounds. MATERIAL AND METHODS Docking studies were performed using the Maestro 12.9 module of Schrodinger software over 70 molecules with RdRp as the target and remdesivir as the standard drug and further confirmed by simulation studies. RESULTS The docking studies showed that many HIV protease inhibitors demonstrated remarkable binding interactions with the target RdRp. Protease inhibitors such as lopinavir and ritonavir are effective. Along with these, AT-527, ledipasvir, bicalutamide, and cobicistat showed improved docking scores. RMSD and RMSF were further analyzed for potent ledipasvir and ritonavir by simulation studies and were identified as potential candidates for corona disease. CONCLUSION The drug repurposing approach provides a new avenue in COVID-19 treatment.
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Affiliation(s)
- Irine Pauly
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Ankit Kumar Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Adarsh Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Yogesh Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Suresh Thareja
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Mohammad A Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jaddah, Saudi Arabia.,Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770, Australia.,Novel Global Community Educational Foundation, Australia Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, Australia
| | - Amita Verma
- Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, 211007, India
| | - Pradeep Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
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2
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Squires KE, Ogilvie L, Jucov A, Anastasiy I, Ghicavii N, Huguet J, Melara R, Constantineau M, De La Rosa A, Mayers DL. A randomized phase 1b trial of the active site polymerase inhibitor nucleotide ATI-2173 in patients with chronic hepatitis B virus infection. J Viral Hepat 2023; 30:19-28. [PMID: 36201354 PMCID: PMC10092119 DOI: 10.1111/jvh.13753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 01/15/2023]
Abstract
ATI-2173 is an active site polymerase inhibitor nucleotide in development as part of a potentially curative regimen for chronic hepatitis B virus (HBV) infection. This study evaluated the safety, tolerability, pharmacokinetics (PK) and antiviral activity of ATI-2173. This was a phase 1b, randomized, double-blind, placebo-controlled trial in treatment-naive adults with chronic HBV infection conducted in the Republic of Moldova and Ukraine (ClinicalTrials.gov: NCT04248426). Patients positive for hepatitis B surface antigen were randomized 6:2 to receive once-daily oral doses of ATI-2173 10, 25, or 50 mg (n = 6 per dose) or placebo (n = 7) for 28 days, with off-treatment monitoring for 24 weeks. Endpoints included PK parameters of ATI-2173 and its metabolite clevudine, maximum reduction from baseline in HBV DNA, and safety and tolerability. Treatment-emergent adverse events occurred in eight patients (47%) receiving ATI-2173 and five (71%) receiving placebo; headache was the most common (n = 4). ATI-2173 PK was generally dose proportional. Systemic clevudine exposure with ATI-2173 dosing was substantially reduced compared with historical values observed with clevudine administration. On Day 28, mean changes from baseline in HBV DNA were -2.72 to -2.78 log10 IU/ml with ATI-2173 and +0.17 log10 IU/ml with placebo. Off-treatment sustained viral suppression and decreases in covalently closed circular DNA biomarkers were observed in most patients; one maintained undetectable HBV DNA at 24 weeks off treatment. In this 28-day monotherapy study, ATI-2173 demonstrated safety and antiviral activity, with sustained off-treatment effects and substantially reduced systemic clevudine exposure. These results support evaluation of ATI-2173 with tenofovir disoproxil fumarate in phase 2 studies.
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Affiliation(s)
| | | | - Alina Jucov
- ARENSIA Exploratory Medicine, Republican Clinical Hospital, Chisinau, Moldova.,Department of Infectious Diseases, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Moldova
| | - Igor Anastasiy
- Department of Infectious Diseases, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Moldova.,ARENSIA Exploratory Medicine, Kiev, Ukraine
| | - Nelli Ghicavii
- ARENSIA Exploratory Medicine, Republican Clinical Hospital, Chisinau, Moldova
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3
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Ruiz Puentes P, Rueda-Gensini L, Valderrama N, Hernández I, González C, Daza L, Muñoz-Camargo C, Cruz JC, Arbeláez P. Predicting target-ligand interactions with graph convolutional networks for interpretable pharmaceutical discovery. Sci Rep 2022; 12:8434. [PMID: 35589824 PMCID: PMC9119967 DOI: 10.1038/s41598-022-12180-x] [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: 01/14/2022] [Accepted: 05/05/2022] [Indexed: 02/08/2023] Open
Abstract
Drug Discovery is an active research area that demands great investments and generates low returns due to its inherent complexity and great costs. To identify potential therapeutic candidates more effectively, we propose protein–ligand with adversarial augmentations network (PLA-Net), a deep learning-based approach to predict target–ligand interactions. PLA-Net consists of a two-module deep graph convolutional network that considers ligands’ and targets’ most relevant chemical information, successfully combining them to find their binding capability. Moreover, we generate adversarial data augmentations that preserve relevant biological backgrounds and improve the interpretability of our model, highlighting the relevant substructures of the ligands reported to interact with the protein targets. Our experiments demonstrate that the joint ligand–target information and the adversarial augmentations significantly increase the interaction prediction performance. PLA-Net achieves 86.52% in mean average precision for 102 target proteins with perfect performance for 30 of them, in a curated version of actives as decoys dataset. Lastly, we accurately predict pharmacologically-relevant molecules when screening the ligands of ChEMBL and drug repurposing Hub datasets with the perfect-scoring targets.
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Affiliation(s)
- Paola Ruiz Puentes
- Center for Research and Formation in Artificial Intelligence, Universidad de los Andes, Bogotá, 111711, Colombia.,Department of Biomedical Engineering, Universidad de los Andes, Bogotá, 111711, Colombia
| | - Laura Rueda-Gensini
- Center for Research and Formation in Artificial Intelligence, Universidad de los Andes, Bogotá, 111711, Colombia.,Department of Biomedical Engineering, Universidad de los Andes, Bogotá, 111711, Colombia
| | - Natalia Valderrama
- Center for Research and Formation in Artificial Intelligence, Universidad de los Andes, Bogotá, 111711, Colombia.,Department of Biomedical Engineering, Universidad de los Andes, Bogotá, 111711, Colombia
| | - Isabela Hernández
- Center for Research and Formation in Artificial Intelligence, Universidad de los Andes, Bogotá, 111711, Colombia.,Department of Biomedical Engineering, Universidad de los Andes, Bogotá, 111711, Colombia
| | - Cristina González
- Center for Research and Formation in Artificial Intelligence, Universidad de los Andes, Bogotá, 111711, Colombia.,Department of Biomedical Engineering, Universidad de los Andes, Bogotá, 111711, Colombia
| | - Laura Daza
- Center for Research and Formation in Artificial Intelligence, Universidad de los Andes, Bogotá, 111711, Colombia.,Department of Biomedical Engineering, Universidad de los Andes, Bogotá, 111711, Colombia
| | - Carolina Muñoz-Camargo
- Department of Biomedical Engineering, Universidad de los Andes, Bogotá, 111711, Colombia
| | - Juan C Cruz
- Department of Biomedical Engineering, Universidad de los Andes, Bogotá, 111711, Colombia
| | - Pablo Arbeláez
- Center for Research and Formation in Artificial Intelligence, Universidad de los Andes, Bogotá, 111711, Colombia. .,Department of Biomedical Engineering, Universidad de los Andes, Bogotá, 111711, Colombia.
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Gish RG, Asselah T, Squires K, Mayers D. Active site polymerase inhibitor nucleotides (ASPINs): Potential agents for chronic HBV cure regimens. Antivir Chem Chemother 2022; 30:20402066221138705. [PMID: 36423233 PMCID: PMC9703507 DOI: 10.1177/20402066221138705] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 10/06/2022] [Indexed: 10/03/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection affects 240 to 300 million people worldwide. In the nucleus of infected hepatocytes, the HBV genome is converted to covalently closed circular DNA (cccDNA), which persists and serves as a transcriptional template for viral progeny. Therefore, a long-term cure for chronic HBV infection will require elimination of cccDNA. Although currently available nucleos(t)ide analogues (eg, tenofovir disoproxil fumarate, tenofovir alafenamide, entecavir) effectively control HBV replication, they are seldom curative (functional cure rate ∼10%) and require lifelong treatment for most patients. As such, antiviral agents with novel mechanisms of action are needed. Active site polymerase inhibitor nucleotides (ASPINs) noncompetitively distort the HBV polymerase active site to completely inhibit all polymerase functions, unlike traditional chain-terminating nucleos(t)ide analogues, which only target select polymerase functions and are consumed in the process. Clevudine, a first-generation ASPIN, demonstrated potent and prolonged HBV suppression in phase 2 and 3 clinical studies, but long-term treatment was associated with reversible myopathy in a small number of patients. ATI-2173, a novel next-generation ASPIN, is structurally similar to clevudine but targets the liver and demonstrates potent anti-HBV activity on and off treatment, and may ultimately demonstrate an improved pharmacokinetic and safety profile by significantly reducing systemic clevudine exposure. Thus, ATI-2173 is currently in clinical development as an agent for HBV cure. Here, we review the mechanism of action and preclinical and clinical profiles of clevudine and ATI-2173 to support the role of ASPINs as part of curative regimens for chronic HBV infection.
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Affiliation(s)
- Robert G Gish
- Hepatitis B Foundation, Doylestown, PA, USA
- Robert G. Gish Consultants, LLC, La Jolla, CA, USA
| | - Tarik Asselah
- Université de Paris, Inserm U1149, Centre de Recherche sur l’inflammation, Paris, France
- Department of Hepatology, AP-HP, Hôpital Beaujon, Clichy, France
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5
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Singh US, Mulamoottil VA, Chu CK. Synthesis of an Anti-hepatitis B Agent, 2'-Fluoro-6'-methylene-carbocyclic Adenosine (FMCA) and Its Phosphoramidate (FMCAP). J Org Chem 2019; 84:752-759. [PMID: 30589264 DOI: 10.1021/acs.joc.8b02599] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
2'-Fluoro-6'-methylene-carbocyclic adenosine (FMCA, 12) and its phosphoramidate prodrug (FMCAP, 14) have been proven as a potential anti-HBV agent against both adefovir-resistant as well as lamivudine-resistant double (rtL180M/rtM204V) mutants. Furthermore, in vitro, these agents have demonstrated significant activity against lamivudine/entecavir triple mutants (L180M + S202G + M204V). These preliminary results encourage us for further biological evaluation of FMCA and FMCAP to develop as a potential clinical candidate as an anti-HBV agent, which may overcome the problem of drug resistance in HBV therapy. To support the preclinical exploration, a scalable synthesis of this molecule was needed. In this communication, a practical and scalable synthesis of FMCA, and its prodrug, is reported via ketone 1. The selective opening of the isopropylidene group of 2 led to compound 3. Protection of the allylic hydroxyl group of 3, followed by fluorination and deprotection, afforded the key intermediate 10, which was condensed with a Boc-protected adenine, followed by deprotection, furnished the target nucleoside FMCA (12) in high yield. Further coupling of phosphorochloridate of L-alanine isopropyl ester (13) with FMCA gave its phosphoramidate prodrug FMCAP (14) in good yield.
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Affiliation(s)
- Uma S Singh
- The University of Georgia , College of Pharmacy , Athens , Georgia 30602 , United States
| | | | - Chung K Chu
- The University of Georgia , College of Pharmacy , Athens , Georgia 30602 , United States
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6
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Ricaforte-Campos JD, Benjamin CLM, Nikolova D, Gluud C. Clevudine in people with chronic hepatitis B virus infection. Hippokratia 2016. [DOI: 10.1002/14651858.cd012411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Jane D Ricaforte-Campos
- ManilaMed (Medical Center Manila); Section of Gastroenterogy, Department of Internal Medicine Manila; General Luna 1122 Ermita Manila Philippines 1000
| | - Cherry Lois M Benjamin
- ManilaMed (Medical Center Manila); Section of Gastroenterogy, Department of Internal Medicine Manila; General Luna 1122 Ermita Manila Philippines 1000
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital; The Cochrane Hepato-Biliary Group; Blegdamsvej 9 Copenhagen Denmark DK-2100
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital; The Cochrane Hepato-Biliary Group; Blegdamsvej 9 Copenhagen Denmark DK-2100
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7
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Chong Y, Stuyver L, Otto MJ, Schinazi RF, Chu CK. Mechanism of Antiviral Activities of 3′-Substituted L-Nucleosides against 3Tc-Resistant HBV Polymerase: A Molecular Modelling Approach. ACTA ACUST UNITED AC 2016; 14:309-19. [PMID: 14968937 DOI: 10.1177/095632020301400603] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Comparison of the active sites of the human HIV-1 reverse transcriptase (RT) and the homology-modelled hepatitis B virus (HBV) polymerase shows that the active sites of both enzymes are open to L-nucleosides, but the position where the 3′-substituent of the L-ribose projects in HBV polymerase is wider and deeper than HIV-1 RT, which enables the HBV polymerase to accommodate various 3′-substituted L-nucleosides. However, the space is not sufficient to accommodate a bulky 3′-substituent such as the 3′-azido group of L-3′-azido-3′-deoxythymidine. Analysis of the minimized structure of rtM204V HBV polymerase/ 3TCTP complex shows that, instead of the steric stress produced by rtV204, a loss of the van der Waals contact around the oxathiolane sugar moiety of 3TCTP caused by the mutation results in the disruption of the active site. Therefore, nucleosides, which are stabilized by additional specific interaction with the enzyme residues, can have more opportunities to circumvent the destabilization by the loss of hydrophobic interaction conferred by mutation. Specifically, the substitution at the 3′-position would be beneficial as the HBV polymerase has wide open space composed of the highly conserved motif (YMDD) where the 3′-substituents of the L-nucleosides project. As an example, our study shows that the 3′-fluorine atom contributes to the antiviral activity of L-3′-Fd4CTP against rtM204V HBV polymerase by readily compensating for the loss of the van der Waals interaction around the 2′,3′-double bond through a formation of a hydrogen bond to the amide backbone of rtD205.
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Affiliation(s)
- Youhoon Chong
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Ga., USA
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8
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Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H. Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II-III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas. Chem Rev 2016; 116:422-518. [PMID: 26756377 DOI: 10.1021/acs.chemrev.5b00392] [Citation(s) in RCA: 1916] [Impact Index Per Article: 212.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Yu Zhou
- Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China
| | - Jiang Wang
- Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China
| | - Zhanni Gu
- Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China
| | - Shuni Wang
- Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China
| | - Wei Zhu
- Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China
| | - José Luis Aceña
- Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU , Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain.,Department of Organic Chemistry, Autónoma University of Madrid , Cantoblanco, 28049 Madrid, Spain
| | - Vadim A Soloshonok
- Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU , Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain.,IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013 Bilbao, Spain
| | - Kunisuke Izawa
- Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, Japan 533-0024
| | - Hong Liu
- Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China
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9
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Morgnanesi D, Heinrichs EJ, Mele AR, Wilkinson S, Zhou S, Kulp JL. A computational chemistry perspective on the current status and future direction of hepatitis B antiviral drug discovery. Antiviral Res 2015; 123:204-15. [PMID: 26477294 DOI: 10.1016/j.antiviral.2015.10.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 10/02/2015] [Accepted: 10/11/2015] [Indexed: 12/11/2022]
Abstract
Computational chemical biology, applied to research on hepatitis B virus (HBV), has two major branches: bioinformatics (statistical models) and first-principle methods (molecular physics). While bioinformatics focuses on statistical tools and biological databases, molecular physics uses mathematics and chemical theory to study the interactions of biomolecules. Three computational techniques most commonly used in HBV research are homology modeling, molecular docking, and molecular dynamics. Homology modeling is a computational simulation to predict protein structure and has been used to construct conformers of the viral polymerase (reverse transcriptase domain and RNase H domain) and the HBV X protein. Molecular docking is used to predict the most likely orientation of a ligand when it is bound to a protein, as well as determining an energy score of the docked conformation. Molecular dynamics is a simulation that analyzes biomolecule motions and determines conformation and stability patterns. All of these modeling techniques have aided in the understanding of resistance mutations on HBV non-nucleos(t)ide reverse-transcriptase inhibitor binding. Finally, bioinformatics can be used to study the DNA and RNA protein sequences of viruses to both analyze drug resistance and to genotype the viral genomes. Overall, with these techniques, and others, computational chemical biology is becoming more and more necessary in hepatitis B research. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B."
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Affiliation(s)
- Dante Morgnanesi
- Department of Chemistry, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - Eric J Heinrichs
- Department of Chemistry, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - Anthony R Mele
- Department of Chemistry, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - Sean Wilkinson
- Department of Chemistry, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - Suzanne Zhou
- Department of Chemistry, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - John L Kulp
- Department of Chemistry, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA.
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10
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Clark DN, Hu J. Hepatitis B virus reverse transcriptase - Target of current antiviral therapy and future drug development. Antiviral Res 2015; 123:132-7. [PMID: 26408354 DOI: 10.1016/j.antiviral.2015.09.011] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 09/09/2015] [Accepted: 09/21/2015] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) infections rely on the proper functioning of the viral polymerase enzyme, a specialized reverse transcriptase (RT) with multiple activities. All currently approved antiviral drugs for the treatment of chronic HBV infection, except for interferon, target the RT and belong to the same chemical class - they are all nucleoside analogs. Viral DNA synthesis is carried out by the RT enzyme in several different steps, each with distinct RT conformational requirements. In principle, each stage may be targeted by distinct antiviral drugs. In particular, the HBV RT has the unique ability to initiate viral DNA synthesis using itself as a protein primer in a novel protein priming reaction. In order to help identify RT inhibitors and study their mechanisms of action, a number of experimental systems have been developed, each varying in its ability to dissect the protein priming stage and subsequent stages of viral DNA synthesis at the molecular level. Two of the most effective drugs to date, entecavir and tenofovir, can inhibit both the protein priming and the subsequent DNA elongation stages of HBV DNA synthesis. Interestingly, clevudine, a thymidine analog, can inhibit both protein priming and DNA elongation in a non-competitive manner and without being incorporated into the viral DNA. Thus, a nucleoside RT inhibitor (NRTI) can functionally mimic a non-NRTI (NNRTI) in its inhibition of the HBV RT. Therefore, novel NRTIs as well as NNRTIs may be developed to inhibit the DNA synthesis activity of the HBV RT. Furthermore, additional activities of the RT that are also essential to HBV replication, including specific recognition of the viral RNA and its packaging into viral nucleocapsids, may be exploited for antiviral development. To achieve a more potent inhibition of viral replication and ultimately cure chronic HBV infection, the next generation of anti-HBV therapies will likely need to include NRTIs, NNRTIs, and other agents that target the viral RT as well as other viral and host factors in various combinations. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B."
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Affiliation(s)
- Daniel N Clark
- Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.
| | - Jianming Hu
- Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
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11
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Gogineni V, Schinazi RF, Hamann MT. Role of Marine Natural Products in the Genesis of Antiviral Agents. Chem Rev 2015; 115:9655-706. [PMID: 26317854 PMCID: PMC4883660 DOI: 10.1021/cr4006318] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Vedanjali Gogineni
- Department of Pharmacognosy, Pharmacology, Chemistry & Biochemistry, University of Mississippi, School of Pharmacy, University, Mississippi 38677, United States
| | - Raymond F. Schinazi
- Center for AIDS Research, Department of Pediatrics, Emory University/Veterans Affairs Medical Center, 1760 Haygood Drive NE, Atlanta, Georgia 30322, United States
| | - Mark T. Hamann
- Department of Pharmacognosy, Pharmacology, Chemistry & Biochemistry, University of Mississippi, School of Pharmacy, University, Mississippi 38677, United States
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12
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Abstract
The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, (18)F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.
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Affiliation(s)
- Eric P Gillis
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Kyle J Eastman
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Matthew D Hill
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - David J Donnelly
- Discovery Chemistry Platforms, PET Radiochemical Synthesis, Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States
| | - Nicholas A Meanwell
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States
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13
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Paintsil E, Cheng YC. Antiviral Agents☆. REFERENCE MODULE IN BIOMEDICAL SCIENCES 2014. [PMCID: PMC7150273 DOI: 10.1016/b978-0-12-801238-3.02387-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Antiviral agents are drugs approved in the USA by the Food and Drug Administration (FDA) for the treatment or control of viral infections. Available antiviral agents mainly target stages in the viral life cycle. The target stages in the viral life cycle are; viral attachment to host cell, uncoating, synthesis of viral mRNA, translation of mRNA, replication of viral RNA and DNA, maturation of new viral proteins, budding, release of newly synthesized virus, and free virus in body fluids. Two important factors that can limit the utility of antiviral drugs are toxicity and the development of resistance to the antiviral agent by the virus. In addition, host phenotypic behaviors toward antiviral drugs because of either genomic or epigenetic factors could limit the efficacy of an antiviral agent in an individual. This article summarizes the most relevant pharmacologic and clinical properties of current antiviral agents, and targets for novel antiviral agents.
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14
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Qiu LP, Chen L, Chen KP. Antihepatitis B therapy: a review of current medications and novel small molecule inhibitors. Fundam Clin Pharmacol 2013; 28:364-81. [DOI: 10.1111/fcp.12053] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2012] [Revised: 09/14/2013] [Accepted: 09/30/2013] [Indexed: 12/18/2022]
Affiliation(s)
- Li-Peng Qiu
- Institute of Life Sciences; Jiangsu University; Zhenjiang Jiangsu Province 212013 China
| | - Liang Chen
- Institute of Life Sciences; Jiangsu University; Zhenjiang Jiangsu Province 212013 China
| | - Ke-Ping Chen
- Institute of Life Sciences; Jiangsu University; Zhenjiang Jiangsu Province 212013 China
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15
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Noncompetitive inhibition of hepatitis B virus reverse transcriptase protein priming and DNA synthesis by the nucleoside analog clevudine. Antimicrob Agents Chemother 2013; 57:4181-9. [PMID: 23774432 DOI: 10.1128/aac.00599-13] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
All currently approved antiviral drugs for the treatment of chronic hepatitis B virus (HBV) infection are nucleos(t)ide reverse transcriptase inhibitors (NRTI), which inhibit the DNA synthesis activity of the HBV polymerase. The polymerase is a unique reverse transcriptase (RT) that has a novel protein priming activity in which HP initiates viral DNA synthesis using itself as a protein primer. We have determined the ability of NRTI-triphosphates (TP) to inhibit HBV protein priming and their mechanisms of action. While entecavir-TP (a dGTP analog) inhibited protein priming initiated specifically with dGTP, clevudine-TP (a TTP analog) was able to inhibit protein priming independently of the deoxynucleoside triphosphate (dNTP) substrate and without being incorporated into DNA. We next investigated the effect of NRTIs on the second stage of protein priming, wherein two dAMP nucleotides are added to the initial deoxyguanosine nucleotide. The obtained results indicated that clevudine-TP as well as tenofovir DF-DP strongly inhibited the second stage of protein priming. Tenofovir DF-DP was incorporated into the viral DNA primer, whereas clevudine-TP inhibited the second stage of priming without being incorporated. Finally, kinetic analyses using the HBV endogenous polymerase assay revealed that clevudine-TP inhibited DNA chain elongation by HP in a noncompetitive manner. Thus, clevudine-TP appears to have the unique ability to inhibit HBV RT via binding to and distorting the HP active site, sharing properties with both NRTIs and nonnucleoside RT inhibitors.
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16
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Alauddin MM. Nucleoside-based probes for imaging tumor proliferation using positron emission tomography. J Labelled Comp Radiopharm 2013; 56:237-43. [PMID: 24285330 DOI: 10.1002/jlcr.3003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Revised: 07/03/2012] [Accepted: 11/06/2012] [Indexed: 02/03/2023]
Abstract
Cancer is one of the leading causes of human death, and early detection can be beneficial for its timely therapy and management. For the early detection of cancer, positron emission tomography (PET) is more accurate and sensitive than other imaging modalities, such as computed tomography and magnetic resonance imaging. [(18) F]-Labeled fluorodeoxyglucose is the most useful PET probe in early detection of cancer; however, its nonspecific accumulation and consequent false-positive findings warrant the identification of other PET probes. Thymidine (TdR) and its analogs have been radiolabeled for PET imaging of cellular proliferation and DNA synthesis. Because of its in vivo instability, radiolabeled TdR has not been successful in PET imaging. However, some of its radiolabeled analogs have been developed for PET imaging of cellular proliferation and DNA synthesis. In this review, the radiochemistry and production of (11) C-TdR and (11) C/(18) F-labeled TdR analogs published to date are presented.
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Affiliation(s)
- Mian M Alauddin
- Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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17
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Dusheiko G. Treatment of HBeAg positive chronic hepatitis B: interferon or nucleoside analogues. Liver Int 2013; 33 Suppl 1:137-50. [PMID: 23286858 DOI: 10.1111/liv.12078] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Interferon alpha has restricted efficacy in as much as only a proportion of patients show a response. However, in appropriately selected HBeAg-positive and HBeAg-negative patients, sustained suppression of viral replication can be achieved, and HBeAg or even HBsAg seroconversion can be attained. Thus, finite course of interferon alpha can be successful, and offer an advantage to patient. Interferon (IFN) remains a benchmark therapy for chronic hepatitis B. The main advantages of IFN-α over nucleoside analogues are the absence of resistance and the possibility of immune-mediated clearance of hepatitis B. Unfortunately, side effects preclude the use of interferon alpha in substantial proportions of patients, and prolonged maintenance therapy to suppress hepatitis B virus (HBV) is not feasible. Nucleoside analogues are given by mouth, once per day, and the safety, potency and efficacy have improved and facilitated treatment. However, maintenance of long-term suppression is required for the majority of patients. In general, treatment of chronic hepatitis B should target patients with active disease and viral replication, preferably before the signs and symptoms of cirrhosis or significant injury has occurred. Current EASL guidelines suggest that treatment be based on the evaluation of three criteria: Serum aminotransferase levels, serum HBV DNA levels and histological grade and stage. Many questions remain unanswered on the optimal treatment of patients with chronic hepatitis B with a nucleoside vs interferon alpha. Both forms of treatment have benefits and the choice should be selected and tailored. Stopping or futility rules can be implemented in patients who fail interferon. Recent data suggest the safety and efficacy of nucleoside analogues in the third trimester of pregnancy to reduce the risk of transmission from mothers to their children.
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Affiliation(s)
- Geoffrey Dusheiko
- UCL Division of Liver and Digestive Health, University College London Medical School, and Royal Free Hospital, London, UK.
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18
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Fung J, Lai CL, Seto WK, Yuen MF. Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B. J Antimicrob Chemother 2011; 66:2715-25. [PMID: 21965435 DOI: 10.1093/jac/dkr388] [Citation(s) in RCA: 137] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The current available agents for the treatment of chronic hepatitis B (CHB) include immunomodulatory agents, such as interferon-α and pegylated interferon-α, and oral nucleoside/nucleotide analogues (NAs), including lamivudine, adefovir, telbivudine, entecavir and tenofovir. The NAs work mainly by inhibiting hepatitis B virus (HBV) DNA polymerase activity and thus suppress HBV replication. Oral NAs have become the mainstay of CHB treatment, mainly due to their profound viral suppressive effects and also due in part to the ease of single daily dosing and lack of significant side effects. One major drawback of NA therapy is the development of drug resistance mutations with long-term treatment. Lamivudine, the first oral NA approved for CHB patients, is associated with high rates of drug resistance, with resultant virological relapse and biochemical flare. Fortunately, newer and more potent NAs, such as entecavir and tenofovir, have very low resistance rates, with potent and durable viral suppression. This review is aimed at the current developments in NAs for CHB treatment, detailing the mechanisms of antiviral activity of the different agents, the efficacy of viral suppression, the achievement of treatment endpoints, the development of drug resistance and the optimal strategies for using these drugs.
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Affiliation(s)
- James Fung
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR
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19
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Jessel S, Meier C. Synthesis of 2′,3′-Modified Carbocyclic L-Nucleoside Analogues. European J Org Chem 2011. [DOI: 10.1002/ejoc.201001473] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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20
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Daga PR, Duan J, Doerksen RJ. Computational model of hepatitis B virus DNA polymerase: molecular dynamics and docking to understand resistant mutations. Protein Sci 2010; 19:796-807. [PMID: 20162615 DOI: 10.1002/pro.359] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Hepatitis B virus (HBV) DNA polymerase (HDP) is a pharmacological target of intense interest. Of the seven agents approved in USA for the treatment of HBV infections, five are HDP inhibitors. However, resistance development against HDP inhibitors, such as lamivudine and adefovir, has severely hurt their efficacy to treat HBV. As a step toward understanding the mechanism of resistance development and for gaining detailed insights about the active site of the enzyme, we have built a homology model of HDP which is an advance over previously reported ones. Validation using various techniques, including PROSTAT, PROCHECK, and Verify-3D profile, proved the model to be stereochemically significant. The stability of the model was studied using a 5 ns molecular dynamics simulation. The model was found to be sufficiently stable after the initial 2.5 ns with overall root mean squared deviation (RMSD) of 4.13 A. The homology model matched the results of experimental mutation studies of HDP reported in the literature, including those of antiviral-resistant mutations. Our model suggests the significant role of conserved residues, such as rtLys32, in binding of the inhibitors, contrary to previous studies. The model provides an explanation for the inactivity of some anti-HIV molecules which are inactive against HDP. Conformational changes which occurred in certain binding pocket amino acids helped to explain the better binding of some of the inhibitors in comparison to the substrates.
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Affiliation(s)
- Pankaj R Daga
- Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, Mississippi 38677-1848, USA
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21
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Stein LL, Loomba R. Drug targets in hepatitis B virus infection. Infect Disord Drug Targets 2009; 9:105-16. [PMID: 19275699 DOI: 10.2174/187152609787847677] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus infection (HBV) is a significant global health problem. Despite the success of universal hepatitis B vaccination in many countries, more than 350 million individuals worldwide are chronically infected and 15- 40% of those will develop cirrhosis and/or hepatocellular carcinoma if left untreated. Available therapies for chronic hepatitis B (CHB) infection are effective at decreasing viremia and improving measured clinical outcomes, however, no single therapy is optimal. As such, alternative drug therapies and the investigation of their role in the management of CHB are warranted. Significant improvements in the understanding of the HBV life cycle, viral genomics, and virus-host interactions continue to lead to the development of novel viral targets and immune modulators. Currently, two major classes of agents are utilized in CHB: the interferons and the nucleos(t)ide analogues. Each agent has individual advantages and drawbacks. The development of specific antiviral therapy has led to the emergence of HBV drug-resistant strains that has limited the long-term therapeutic potential of available agents. This necessitates the development of new agents that target both wild-type and drug-resistant strains. Further understanding of the basic mechanisms and clinical nuances of drug therapy is warranted. As most novel therapies are in the earliest stages of clinical development and testing, in the near future, treatment will continue to be long-term and likely involve the use of combination therapies to prevent viral resistance. In this review, we will highlight the HBV life cycle and genome, focusing in on current and potential novel antiviral drug targets as well as the benefits and clinical challenges with these therapies.
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Affiliation(s)
- Lance L Stein
- Division of Gastroenterology, Department of Medicine, University of California - San Diego, CA, USA
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22
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Sharon A, Chu CK. Understanding the molecular basis of HBV drug resistance by molecular modeling. Antiviral Res 2008; 80:339-53. [PMID: 18765256 PMCID: PMC2626186 DOI: 10.1016/j.antiviral.2008.07.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2008] [Revised: 07/25/2008] [Accepted: 07/29/2008] [Indexed: 12/30/2022]
Abstract
Despite the significant successes in the area of anti-HBV agents, resistance and cross-resistance against available therapeutics are the major hurdles in drug discovery. The present investigation is to understand the molecular basis of drug resistance conferred by the B and C domain mutations of HBV-polymerase on the binding affinity of five anti-HBV agents [lamivudine (3TC, 1), adefovir (ADV, 2), entecavir (ETV, 3), telbivudine (LdT, 4) and clevudine (l-FMAU, 5)]. In this regard, homology modeled structure of HBV-polymerase was used for minimization, conformational search and induced fit docking followed by binding energy calculation on wild-type as well as on mutant HBV-polymerases (L180M, M204V, M204I, L180M+M204V, L180M-M204I). Our studies suggest a significant correlation between the fold resistances and the binding affinity of anti-HBV nucleosides. The binding mode studies reveals that the domain C residue M204 is closely associated with sugar/pseudosugar ring positioning in the active site. The positioning of oxathiolane ring of 3TC (1) is plausible due the induced fit orientation of the M204 residue in wild-type, and further mutation of M204 to V204 or I204 reduces the final binding affinity which leads to the drug resistance. The domain B residue L180 is not directly close ( approximately 6A) to the nucleoside/nucleoside analogs, but indirectly associated with other active-site hydrophobic residues such as A87, F88, P177 and M204. These five hydrophobic residues can directly affect on the incoming nucleoside analogs in terms of its association and interaction that can alter the final binding affinity. There was no sugar ring shifting observed in the case of adefovir (2) and entecavir (3), and the position of sugar ring of 2 and 3 is found similar to the sugar position of natural substrate dATP and dGTP, respectively. The exocyclic double bond of entecavir (3) occupied in the backside hydrophobic pocket (made by residues A87, F88, P177, L180 and M204), which enhances the overall binding affinity. The active site binding of LdT (4) and l-FMAU (5) showed backward shifting along with upward movement without enforcing M204 residue and this significant different binding mode makes these molecules as polymerase inhibitors, without being incorporated into the growing HBV-DNA chain. Structural results conferred by these l- and d-nucleosides, explored the molecular basis of drug resistance which can be utilized for future anti-HBV drug discovery.
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Affiliation(s)
- Ashoke Sharon
- The University of Georgia College of Pharmacy, Athens, GA 30602, USA
| | - Chung K. Chu
- The University of Georgia College of Pharmacy, Athens, GA 30602, USA
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23
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Asselah T, Lada O, Moucari R, Marcellin P. Clevudine: a promising therapy for the treatment of chronic hepatitis B. Expert Opin Investig Drugs 2008; 17:1963-74. [PMID: 19012511 DOI: 10.1517/13543780802535760] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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24
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Nishii R, Volgin AY, Mawlawi O, Mukhopadhyay U, Pal A, Bornmann W, Gelovani JG, Alauddin MM. Evaluation of 2'-deoxy-2'-[18F]fluoro-5-methyl-1-beta-L: -arabinofuranosyluracil ([18F]-L: -FMAU) as a PET imaging agent for cellular proliferation: comparison with [18F]-D: -FMAU and [18F]FLT. Eur J Nucl Med Mol Imaging 2008; 35:990-8. [PMID: 18057932 DOI: 10.1007/s00259-007-0649-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2007] [Accepted: 10/23/2007] [Indexed: 02/03/2023]
Abstract
PURPOSE Clevudine (L: -FMAU) an un-natural analogue of thymidine, is in clinical trials for the treatment of hepatitis B virus (HBV). L: -FMAU is phosphorylated by cellular kinases such as thymidine kinase 1 and deoxycytidine kinase, and its triphosphate form inhibits HBV deoxyribonucleic acid synthesis. Thus, L: -FMAU, radiolabeled with an appropriate isotope, may be useful for positron emission tomography (PET) imaging of tumor proliferation. We evaluated [18F]-L-FMAU as a PET imaging agent in tumor-bearing mice and compared the results with those of two other radiotracers, [18F]-d-FMAU and [18F]-FLT. METHODS Subcutaneous xenografts of the human lung cancer cell lines H441 and H3255 were established in mice. A micro-PET scanner was used to obtain images of the tumor-bearing animals with [18F]-L-FMAU, [18F]-D-FMAU, and [18F]-FLT. RESULTS At 2 h postinjection, the tumor uptake (% ID/g) of 18F]-L: -FMAU, 18F]-D: -FMAU, and [18F]-FLT in the faster-growing H441 cells was 3.13 +/- 1.11, 7.74 +/- 1.39, and 5.10 +/- 1.45, respectively. The corresponding values for the slower-growing H3255 cells were 1.38 +/- 0.81, 4.49 +/- 1.08, and 0.57 +/- 0.33. Tumor/muscle ratios of accumulation for [18F]-L: -FMAU, [18F]-D: -FMAU, and [18F]-FLT in H441 cells were 4.15 +/- 1.82, 3.37 +/- 1.19, and 12.94 +/- 4.38, respectively, and the corresponding values in H3255 cells were 1.62 +/- 0.50, 1.96 +/- 0.74, and 1.50 +/- 0.90. CONCLUSIONS [18F]-L: -FMAU may be a useful agent for imaging tumor proliferation in fast-growing human lung cancers by PET.
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Affiliation(s)
- Ryuichi Nishii
- Department of Experimental Diagnostic Imaging, M. D. Anderson Cancer Center, The University of Texas, Box 059, T8.3895, 1515 Holcombe Blvd, Houston, TX 77030, USA
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25
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Férir G, Kaptein S, Neyts J, De Clercq E. Antiviral treatment of chronic hepatitis B virus infections: the past, the present and the future. Rev Med Virol 2008; 18:19-34. [PMID: 17966115 DOI: 10.1002/rmv.554] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A decade ago, standard therapy against chronic hepatitis B virus infections only consisted of lamivudine or IFN-alpha. Treatment with lamivudine and IFN has been compounded by, respectively, the emergence of drug-resistant virus strains and the appearance of serious side effects. In the last 10 years, hepatitis B treatment has made much progress. Several treatments are now licensed for the treatment of patients with chronic hepatitis B and others are under development. Here, we provide an overview of the potential and mode of action of anti-HBV agents that are currently available, and/or may become available in the near future. Foremost among these newer compounds are adefovir dipivoxil, entecavir and telbivudine.
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Affiliation(s)
- Geoffrey Férir
- Rega Institute for Medical Research, KULeuven, Leuven, Belgium
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26
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Mukhopadhyay U, Pal A, Gelovani JG, Bornmann W, Alauddin MM. Radiosynthesis of 2'-deoxy-2'-[18F]-fluoro-5-methyl-1-beta-L-arabinofuranosyluracil ([18F]-L-FMAU) for PET. Appl Radiat Isot 2007; 65:941-6. [PMID: 17517516 DOI: 10.1016/j.apradiso.2007.04.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2007] [Revised: 03/06/2007] [Accepted: 04/02/2007] [Indexed: 10/23/2022]
Abstract
Radiosynthesis of 2'-deoxy-2'-[(18)F]-fluoro-5-methyl-1-beta-L-arabinofuranosyluracil ([(18)F]-L-FMAU) is reported. Compound 1 was synthesized and converted to 2-triflate 2. Compound 3 was prepared from 2 using tetrabutylammonium[(18)F]fluoride, converted to 4, and then coupled with 5. The crude product was hydrolyzed, and purified by HPLC to obtain 7a. The radiochemical yield of [(18)F]-L-FMAU was 26% decay corrected (d.c.) in four runs with radiochemical purity >99% and specific activity 2200 mCi/micromol. The synthesis time was 3.3-3.5h from the end of bombardment (EOB).
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Affiliation(s)
- Uday Mukhopadhyay
- Department of Experimental Diagnostic Imaging, University of Texas M D Anderson Cancer Center, Houston, TX, USA
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27
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Abstract
Currently approved treatments for hepatitis B virus (HBV) infection include the immunomodulatory agent, IFN-α, and nucleos(t)ide analogues. Their efficacy is limited by their side effects, as well as the induction of viral mutations that render them less potent. It is thus necessary to develop drugs that target additional viral antigens. Chemicals and biomaterials by unique methods of preventing HBV replication are currently being developed, including novel nucleosides and newly synthesized compounds such as capsid assembling and mRNA transcription inhibitors. Molecular therapies that target different stages of the HBV life cycle will aid current methods to manage chronic hepatitis B (CHB) infection. The use of immunomodulators and gene therapy are also under consideration. This report summarizes the most recent treatment possibilities for CHB infection. Emerging therapies and their potential mechanisms, efficacy, and pitfalls are discussed.
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Affiliation(s)
- Guo-Yi Wu
- Hepatology Institute, People's Hospital, Peking University, Beijing 100044, China
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28
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Korba BE, Furman PA, Otto MJ. Clevudine: a potent inhibitor of hepatitis B virus in vitro and in vivo. Expert Rev Anti Infect Ther 2006; 4:549-61. [PMID: 17009935 DOI: 10.1586/14787210.4.4.549] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Clevudine (CLV) is a nucleoside analog of the unnatural L-configuration that has potent anti-hepatitis B virus (HBV) activity in vitro and in vivo with a favorable toxicity profile in all species tested. In cell culture, CLV is readily phosphorylated to the corresponding 5'-triphosphate form of the compound. The mechanism of action of CLV involves the inhibition of the HBV polymerase by CLV 5'-triphosphate. In vivo efficacy studies performed in the duck and woodchuck models showed marked, rapid inhibition of virus replication and no significant toxicity. In the woodchuck model, there was a dose-dependent delay in viral recrudescence and a reduction or loss of covalently closed circular DNA. In Phase II clinical studies, CLV was well tolerated and exhibited potent antiviral activity at all doses investigated. In Phase III studies in both hepatitis B e antigen (HBeAg)-positive and -negative patients, CLV 30 mg administered once daily demonstrated potent antiviral efficacy and significant biochemical improvement after only 24 weeks of therapy. These effects were sustained in a significant portion of the patients when therapy was stopped after 6 months with no viral rebound occurring in approximately 3 and 16% in HBeAg-positive and -negative patients, respectively. There have been no significant safety or tolerance issues associated with the drug in these studies. Future studies will investigate the safety and tolerance of CLV 30 mg given once daily over 48 weeks and longer.
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Affiliation(s)
- Brent E Korba
- Georgetown University Medical Center, Rockville, MD 20850, USA.
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29
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Lee J, Yoo BC, Lee HS, Yoo HW, Yoo HH, Kang MJ, Kim DH. Rapid quantitative determination of L-FMAU-TP from human peripheral-blood mononuclear cells of hepatitis B virus-infected patients treated with L-FMAU by ion-pairing, reverse-phase, liquid chromatography/electrospray tandem mass spectrometry. Ther Drug Monit 2006; 28:131-7. [PMID: 16418707 DOI: 10.1097/01.ftd.0000194027.12107.11] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The purpose of this study was to develop an analytical method for the determination of 2'-fluoro-5-methyl-beta-l-arabinofuranosyl uracil triphosphate (L-FMAU-TP) in human peripheral blood mononuclear cells (PBMCs), and its application in the determination of cellular levels of L-FMAU-TP in PBMCs isolated from patients treated with 2'-fluoro-5-methyl-beta-l-arabinofuranosyl uracil (L-FMAU). An ion-pairing liquid chromatography (IPC) method, coupled with negative ion electrospray ionization tandem mass spectrometry (ESI-MS/MS), was developed for the accurate and repeatable detection of L-FMAU-TP, with a limit of detection of 1.6 pmol/10 cells. The calibration curve for L-FMAU-TP was linear over the concentration range 1.6 to 80 pmol/10(6) cells. The intra- and inter-day precision was lower than 11.2%, and the accuracy was between 97.1 and 106.9%. When applied to the determination of L-FMAU-TP in PBMCs isolated from HBV-infected patients undergoing L-FMAU treatment, the levels reached a steady state concentration 4 weeks after daily single oral administration of 20 mg L-FMAU, and these levels were maintained for up to 12 weeks, but then decreased 12 weeks after drug cessation. The terminal half-life of L-FMAU-TP in PBMCs after drug cessation was estimated to be 15.6 days.
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Affiliation(s)
- Jaeick Lee
- Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Chungryang, Seoul, Korea
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30
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Choo H, Chen X, Yadav V, Wang J, Schinazi RF, Chu CK. Synthesis and anti-HIV activity of D- and L-thietanose nucleosides. J Med Chem 2006; 49:1635-47. [PMID: 16509580 PMCID: PMC2533431 DOI: 10.1021/jm050912h] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Various D- and L-thietanose nucleosides were synthesized from D- and L-xylose. The four-membered thietane ring was efficiently synthesized by the cyclization of 1-thioacetyl-3-mesylate (4/38) under basic conditions. Condensation with various heterocyclic bases was conducted via Pummerer-type rearrangement to afford various nucleoside derivatives. Among the synthesized nucleosides, D-uridine (23), D-cytidine (24), D-5-fluorocytidine (25), and L-cytidine (52) analogues showed moderate anti-HIV activity, with EC50 = 6.9, 1.3, 5.8, and 14.1 microM, respectively. However, these four nucleoside analogues are cytotoxic in peripheral blood mononuclear and CEM cells. The other nucleosides are neither active nor cytotoxic. Interestingly, the oxetanocin A analogue 33 was not active. Comparison of the minimized reverse transcriptases (RTs) complexed with the corresponding triphosphates of the cytidine analogue 24 and the adenosine analogue 33 by molecular modeling studies showed that there is no difference in the binding mode of the triphosphate of the cytidine analogue 24 to the active site of HIV-1 RT from that of the triphosphate of the adenosine analogue 33. Modeling studies on the initial monophosphorylation step by deoxycytidine kinase showed that the catalytic efficiency of phosphorylation through a nucleophilic attack of the 4'-hydroxyl group of thietanose on the gamma-phosphate of ATP is diminished in the case of L-cytidine analogue (52) due to the increased distance between the 4'-hydroxyl group and the gamma-phosphate.
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Affiliation(s)
- Hyunah Choo
- The University of Georgia, College of Pharmacy, Athens, GA 30602
| | - Xin Chen
- The University of Georgia, College of Pharmacy, Athens, GA 30602
| | - Vikas Yadav
- The University of Georgia, College of Pharmacy, Athens, GA 30602
| | - Jianing Wang
- The University of Georgia, College of Pharmacy, Athens, GA 30602
| | - Raymond F. Schinazi
- Emory University School of Medicine/Veterans Affairs Medical Center, Decatur, GA 30033
| | - Chung K. Chu
- The University of Georgia, College of Pharmacy, Athens, GA 30602
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31
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Choi SR, Zhuang ZP, Chacko AM, Acton PD, Tjuvajev-Gelovani J, Doubrovin M, Chu DCK, Kung HF. SPECT imaging of herpes simplex virus type1 thymidine kinase gene expression by [(123)I]FIAU(1). Acad Radiol 2005; 12:798-805. [PMID: 16039533 DOI: 10.1016/j.acra.2005.04.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2005] [Revised: 04/07/2005] [Accepted: 04/08/2005] [Indexed: 11/22/2022]
Abstract
RATIONALE AND OBJECTIVES Introduction of suicide genes, such as herpes simplex virus type1 thymidine kinase (HSV1-tk), in tumor cells has provided a useful method for tumor gene therapy. Several L-nucleosides, such as Lamivudine (3TC) and Clevudine (L-FMAU), have been successfully tested as high-potency antiviral agents. To investigate the potential differences between D- and L-isomers of nucleosides, [(125/123)I]-2'-fluoro-2'-deoxy-1beta-D/L-arabino-furanosy-5-iodo-uracil (D/L-FIAU) have been synthesized and evaluated as potential SPECT agents for imaging HSV1-tk gene expression. MATERIALS AND METHODS [(125/123)I]D- and L-FIAU were prepared by iododestannylation of the respective tin precursors with (125/123)I-sodium iodide. In vitro cell uptake studies were performed by incubation of [(125)I]D- and L-FIAU in RG2 cells expressing HSV1-tk (RG2TK+). In vivo studies including biodistribution and SPECT were performed in RG2TK+ and RG2TK- tumor-bearing nude mice using [(123)I]D- and L-FIAU. RESULTS Cell uptake and biodistribution studies indicated that [(125/123)I]L-FIAU did not show any high accumulation (sensitivity) or uptake ratios (selectivity) in HSV1-TK-positive (RG2TK+) tumors as compared to control tumors. In contrast, [(125/123)I]D-FIAU displayed both sensitivity and selectivity to RG2TK+ tumors. The selective in vivo accumulation of [(123)I]D-FIAU increased with time and the tumor uptake ratios (RG2TK+/RG2TK-) for 2, 4, and 24 hours averaged 6.2, 22.7, and 58.8, respectively. High-resolution SPECT of four nude tumor-bearing mice demonstrated a very high uptake of [(123)I]D-FIAU in the RG2TK+ tumor, while no significant tracer accumulation was observed in the RG2TK- tumor and other organs. CONCLUSION The data suggest that only the D-isomer of [(123)I]FIAU is useful for imaging HSV1-tk gene expression in mice by high-resolution SPECT imaging.
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Affiliation(s)
- Seok Rye Choi
- Department of Radiology, University of Pennsylvania, 3700 Market Street, Room 305, Philadelphia, PA 19104, USA
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Yadav V, Chu CK. Molecular mechanisms of adefovir sensitivity and resistance in HBV polymerase mutants: a molecular dynamics study. Bioorg Med Chem Lett 2005; 14:4313-7. [PMID: 15261293 DOI: 10.1016/j.bmcl.2004.05.075] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2004] [Revised: 05/26/2004] [Accepted: 05/27/2004] [Indexed: 12/01/2022]
Abstract
Molecular modeling studies of adefovir diphosphate with the wild type and the mutant HBV polymerase-DNA complex demonstrated that the increase in adefovir sensitivity toward HBV polymerase mutants (rtL180M, rtM204V/I, rtL180M-M204V/I) is a result of increased van der Waals interaction and is supplemented by the decreased affinity of natural substrate toward the mutant HBV polymerase. In the case of rtN236T mutant, loss of two hydrogen bonds accompanied by significant decrease in electrostatic interactions is observed, which explains the observed decrease in drug sensitivity and binding affinity of adefovir diphosphate toward the rtN236T mutant HBV polymerase.
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Affiliation(s)
- Vikas Yadav
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, GA 30602, USA
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Meanwell NA, Serrano-Wu MH, Snyder LB. Chapter 22. Non-HIV antiviral agents. ANNUAL REPORTS IN MEDICINAL CHEMISTRY 2004; 38:213-228. [PMID: 32287463 PMCID: PMC7126470 DOI: 10.1016/s0065-7743(03)38023-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
This chapter focuses on non-HIV antiviral agents. The development of antiviral agents to treat non-HIV infections is largely focused on therapies for the treatment of chronic hepatitis infections B and C. Nucleoside analog continue to be the mainstay of Hepatitis B Virus (HBV) therapeutics. The first small molecule inhibitor of Hepatitis C Virus (HCV), the NS3 protease inhibitor BILN-2061, entered phase 2 clinical trials, producing a striking reduction in viral load in treated individuals. The development of the HCV replicon system and its application to screening for antiviral agents provided tangible benefit with the disclosure of mechanistically and structurally diverse HCV inhibitors. Adefovir dipivoxil has been approved in the United States and the European Union for the treatment of HBV, providing a second small molecule antiviral to add to lamivudine (3TC) and the injectable protein IFNα as the only approved agents for treating HBV infection. The chapter also provides details of the inhibitors of hepatitis B and C virus, the inhibitors of simplex virus and human cytomegalovirus, the inhibitors of respiratory viruses and the inhibitors of West Nile virus and Papilloma virus.
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Affiliation(s)
- Nicholas A Meanwell
- Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute 5 Research Parkway, Wallingford, CT 06492, USA
| | - Michael H Serrano-Wu
- Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute 5 Research Parkway, Wallingford, CT 06492, USA
| | - Lawrence B Snyder
- Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute 5 Research Parkway, Wallingford, CT 06492, USA
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Lam W, Li Y, Liou JY, Dutschman GE, Cheng YC. Reverse transcriptase activity of hepatitis B virus (HBV) DNA polymerase within core capsid: interaction with deoxynucleoside triphosphates and anti-HBV L-deoxynucleoside analog triphosphates. Mol Pharmacol 2004; 65:400-6. [PMID: 14742682 DOI: 10.1124/mol.65.2.400] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The use of L(-)SddC [beta-L-2',3'-dideoxy-3'-thiacytidine (lamivudine, 3TC)] for the treatment of Herpes B virus (HBV) infection is hindered by the emergence of drug-resistance associated with the L526M, L550V, and L526M/M550V mutations of the viral DNA polymerase (DP). The interactions of the anti-HBV compounds 2',3'-dideoxy-2',3'-didehydro-beta-L(-)-5-fluorode-oxycytidine and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil triphosphate with HBV DP and its L(-)SddC-associated mutants have not been studied. The e antigen-negative variant of HBV associated with the G1896A mutation in the precore region has a high prevalence. Its effect on HBV DP is unclear. Because HBV DNA synthesis occurs in the nucleocapsid, we examined the kinetics of the reverse transcriptase activity from wild-type (wt) and mutated DPs with the wt or G1896A-mutated RNA template in the nucleocapsid. The effects of this template mutation on the activities of these L-nucleoside triphosphates were also examined. Results indicated that these DP mutations increased the Km values of deoxy-NTPs and decreased the efficiencies (Vmax/Km) of DPs. The additional L526M mutation increased the efficiency of the M550V-mutated DP but no more than that of the L526M-mutated DP. The G1896A mutation had impacts on the interactions between different DPs and deoxy-NTPs, except dCTP. It also had different impacts on the actions of the L-nucleoside triphosphates toward DPs. The L526M and M550V mutations caused a greater decrease in the Vmax using the wt RNA template compared with the G1896A-mutated template. The L526M, M550V, and L526M/M550V mutations caused varying degrees of resistance to the different M-nucleoside triphosphates.
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Affiliation(s)
- Wing Lam
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
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Krishnan P, Gullen EA, Lam W, Dutschman GE, Grill SP, Cheng YC. Novel role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the activation of L-nucleoside analogs, a new class of anticancer and antiviral agents. J Biol Chem 2003; 278:36726-32. [PMID: 12869554 DOI: 10.1074/jbc.m307052200] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
l-Nucleoside analogs are a new class of clinically active antiviral and anticancer agents. The phosphorylation of these analogs from diphosphate to triphosphate metabolites is crucial for their biological action. We studied the role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the metabolism of l-nucleoside analogs, using small interfering RNAs to down-regulate the amount of this enzyme in HelaS3 and 2.2.15 cells, chosen as models for studying the impact of the enzyme on the anticancer and antihepatitis B virus activities of these analogs. Decrease in the expression of 3-phosphoglycerate kinase led to a corresponding decrease in the formation of the triphosphate metabolites of l-nucleoside analogs (but not d-nucleoside analogs), resulting in detrimental effects on their activity. The enzyme is important for generating as well as maintaining the steady state levels of l-nucleotides in the cells, thereby playing a key role in the activity of l-nucleoside analogs against human immunodeficiency virus, hepatitis B virus, and cancer. This study also indicates a structure-based distinction in the metabolism of l- and d-nucleoside analogs, disputing the classic notion that nucleoside diphosphate kinases are responsible for the phosphorylation of all classes of nucleoside analog diphosphates.
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Affiliation(s)
- Preethi Krishnan
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
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Raney AK, Hamatake RK, Hong Z. Agents in clinical development for the treatment of chronic hepatitis B. Expert Opin Investig Drugs 2003; 12:1281-95. [PMID: 12882617 DOI: 10.1517/13543784.12.8.1281] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Chronic hepatitis B remains a public health problem of global importance despite the availability of an effective vaccine. Between 350 and 400 million people, approximately 6% of the world's population, suffer from chronic hepatitis B and face a 30% likelihood of developing cirrhotic liver disease or hepatocellular carcinoma. Current treatment options include three monotherapies of subcutaneous interferon, oral nucleoside lamivudine and oral nucleotide adefovir dipivoxil. Unfortunately, these agents have not effectively and frequently been able to attain a 'cure' or complete eradication of the virus. Consequently, the expectation of current therapies is confined to the achievement of clinically beneficial and durable responses defined by lasting suppression of virus replication, histological improvement and increased survival for patients with decompensated liver diseases. Other disadvantages include the undesirable tolerability of interferon, the rapid resistance to lamivudine and the compromise between efficacy and toxicity that led to the development of the 10 mg dose of adefovir dipivoxil. Clearly, better therapeutics and treatment strategies are needed. Increased potency, activity against current treatment-refractory viruses, as well as efficacy in difficult-to-treat populations will be critical to meeting the therapeutic challenge of chronic hepatitis B.
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Affiliation(s)
- Anneke K Raney
- Ribapharm, Inc, Drug Discovery, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA.
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Choo H, Chong Y, Chu CK. The role of 2',3'-unsaturation on the antiviral activity of anti-HIV nucleosides against 3TC-resistant mutant (M184V). Bioorg Med Chem Lett 2003; 13:1993-6. [PMID: 12781181 DOI: 10.1016/s0960-894x(03)00330-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Molecular modeling studies show that the 2',3'-double bond of the sugar moiety of various 2',3'-unsaturated nucleosides interacts with the aromatic moiety of Tyr115 of HIV-1 reverse transcriptase (RT) by hydrophobic pi-pi interaction. In 3TC-resistant mutant (M184V) RT, 2'-fluoro-2',3'-unsaturated nucleosides with a bulky 4'-substituent experience significant steric hindrance with the side chain of Val184.
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Affiliation(s)
- Hyunah Choo
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, GA 30602, USA
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