Abstract
HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent most promising anti- AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). They have a unique antiviral potency, high specificity and low cytotoxicity. However, to a great extent, the efficacy of HIV-1 NNRTIs is compounded by rapid emergence of drug resistant virus strains, which calls for continuous efforts to develop novel HIV-1 NNRTIs. Diarylpyrimidine (DAPY) derivatives, one family of NNRTIs with superior activity profiles against wild-type HIV-1 and mutant strains, have attracted considerable attention over the past few years. Among the potent lead DAPY compounds, etravirine was approved by FDA in January 2008, and its analogue rilpivirine (TMC278) has advanced to phase III clinical trials. The successful development of DAPYs results from a multidisciplinary approach involving traditional medicinal chemistry, structural biology, crystallography and computational chemistry. Recently, a number of novel characteristics of DAPYs including conformational flexibility, positional adaptability, key hydrogen bonds and specifically targeting conserved residues of RT, have been identified, providing valuable avenues for further optimization and development of new DAPY analogues as promising anti-HIV drug candidates. In this review, we first present a brief historical account of the medicinal chemistry of the DAPY NNRTIs, then focus on the extensive structural modifications, SAR studies, and binding mode analysis based on crystallographic and molecular modeling. Other structural related NNRTI scaffolds will also be reviewed.
Keywords: HIV-1, NNRTIs, DAPY, TMC125, TMC278, drug design, drug-resistance, Acquired immune deficiency syndrome (AIDS), vaccine, deaths, pandemic diseases, highly ac-tive antiretroviral therapy (HAART), cytotoxicity, nucleoside re-verse transcriptase inhibitors (NRTIs), potency, pharmacokinetic, di-arylpyrimidine, ligand binding, crystallography, computa-tional chemistry, DAPY NNRTIS, aryl groups, imidoyl thiourea, vaginal HIV microbicide, X-ray crystallographic, torsional flexibility, pyrazinones, Free energy perturbation
Current Medicinal Chemistry
Title: Recent Advances in DAPYs and Related Analogues as HIV-1 NNRTIs
Volume: 18 Issue: 3
Author(s): Xuwang Chen, Peng Zhan, Dongyue Li, Erik De Clercq and Xinyong Liu
Affiliation:
Keywords: HIV-1, NNRTIs, DAPY, TMC125, TMC278, drug design, drug-resistance, Acquired immune deficiency syndrome (AIDS), vaccine, deaths, pandemic diseases, highly ac-tive antiretroviral therapy (HAART), cytotoxicity, nucleoside re-verse transcriptase inhibitors (NRTIs), potency, pharmacokinetic, di-arylpyrimidine, ligand binding, crystallography, computa-tional chemistry, DAPY NNRTIS, aryl groups, imidoyl thiourea, vaginal HIV microbicide, X-ray crystallographic, torsional flexibility, pyrazinones, Free energy perturbation
Abstract: HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent most promising anti- AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). They have a unique antiviral potency, high specificity and low cytotoxicity. However, to a great extent, the efficacy of HIV-1 NNRTIs is compounded by rapid emergence of drug resistant virus strains, which calls for continuous efforts to develop novel HIV-1 NNRTIs. Diarylpyrimidine (DAPY) derivatives, one family of NNRTIs with superior activity profiles against wild-type HIV-1 and mutant strains, have attracted considerable attention over the past few years. Among the potent lead DAPY compounds, etravirine was approved by FDA in January 2008, and its analogue rilpivirine (TMC278) has advanced to phase III clinical trials. The successful development of DAPYs results from a multidisciplinary approach involving traditional medicinal chemistry, structural biology, crystallography and computational chemistry. Recently, a number of novel characteristics of DAPYs including conformational flexibility, positional adaptability, key hydrogen bonds and specifically targeting conserved residues of RT, have been identified, providing valuable avenues for further optimization and development of new DAPY analogues as promising anti-HIV drug candidates. In this review, we first present a brief historical account of the medicinal chemistry of the DAPY NNRTIs, then focus on the extensive structural modifications, SAR studies, and binding mode analysis based on crystallographic and molecular modeling. Other structural related NNRTI scaffolds will also be reviewed.
Export Options
About this article
Cite this article as:
Chen Xuwang, Zhan Peng, Li Dongyue, De Clercq Erik and Liu Xinyong, Recent Advances in DAPYs and Related Analogues as HIV-1 NNRTIs, Current Medicinal Chemistry 2011; 18 (3) . https://dx.doi.org/10.2174/092986711794839142
DOI https://dx.doi.org/10.2174/092986711794839142 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
HIV-1 gp41 as a Target for Viral Entry Inhibition
Current Pharmaceutical Design The Role of Corticosteroids in Sepsis and Acute Respiratory Distress Syndrome
Current Respiratory Medicine Reviews Malaria Chemotherapy: Recent Advances in Drug Development
Recent Patents on Anti-Infective Drug Discovery Multi-Shift Single-Vehicle Routing Problem Under Fuzzy Uncertainty During the COVID-19 Pandemic
Journal of Fuzzy Logic and Modeling in Engineering Aromaticity in Polyacenes and Their Structural Analogues
Current Organic Chemistry Piperidin-4-one: The Potential Pharmacophore
Mini-Reviews in Medicinal Chemistry Heme Oxygenase-1 in Lung Disease
Current Drug Targets Recent Developments in Oxazole Derivatives as Anticancer Agents: Review on Synthetic Strategies, Mechanism of Action and SAR Studies
Anti-Cancer Agents in Medicinal Chemistry Antibacterial and Antiviral Agents: Computational Insight
Current Topics in Medicinal Chemistry Pharmacophore Based 3DQSAR of Phenothiazines as Specific Human Butyrylcholinesterase Inhibitors for Treatment of Alzheimer’s Disease
Current Computer-Aided Drug Design Selected Natural and Synthetic Agents Effective against Parkinson’s Disease with Diverse Mechanisms
Current Topics in Medicinal Chemistry The Mouse Model of Chlamydia Genital Tract Infection: A Review of Infection, Disease, Immunity and Vaccine Development
Current Molecular Medicine In Vitro Cytochrome P450 Inhibition and Induction
Current Drug Metabolism Hidden Hunger of Vitamin E among Healthy College Students: A Cross- Sectional Study
Endocrine, Metabolic & Immune Disorders - Drug Targets <i>In Silico</i> Study Examining New Phenylpropanoids Targets with Antidepressant Activity
Current Drug Targets Preface [Hot Topic: New Clinical Applications for Naturally Occurring Peptide Toxins (Guest Editors: Robert Jones / Graeme Semple)]
Current Medicinal Chemistry 5-HT6 Receptor Antagonists as Potential Therapeutics for Cognitive Impairment
Current Topics in Medicinal Chemistry Mechanochemical Synthesis and Reactivity of 1,2,3-Triazole Carbohydrate Derivatives as Glycogen Phosphorylase Inhibitors
Current Organic Synthesis BDZs, Designer BDZs and Z-drugs: Pharmacology and Misuse Insights
Current Pharmaceutical Design Targeted Delivery of CRISPR/Cas13 as a Promising Therapeutic Approach to Treat SARS-CoV-2
Current Pharmaceutical Biotechnology