Abstract
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are very potent and most promising anti-AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). However, to a great extent, the efficacy of NNRTI drugs is impaired by rapid emergence of drug-resistance mutations. Fortunately, detailed analysis of a wide range of crystal structures of HIV-1 RT/NNRTI complexes together with data on drug resistance mutations has identified factors important for design of inhibitors and resilience to mutations, such as, exhibiting conformational flexibility and positional adaptability of NNRTIs, forming extensive main chain hydrogen bonding, targeting highly conserved residues in HIV-1 RT and possessing unconventional mechanisms for NNRTI-mediated inhibition of RT. Besides, the plasticity of NNRTIs binding pocket (NNIBP) also provides a broad space for the discovery of new generations of NNRTIs. For instance, the composite binding pocket, integrating all available crystal structure information about the NNRTI binding site of HIV RT, was demonstrated to be an effective tool to better understand the flexible nature of the binding pocket and to identify specific inhibitors. The RT/solvent interface proved to be an attractive site for incorporating a moiety to improve water solubility and pharmacokinetics or introducing a second pharmacophore to construct multifunctional ligand. Totally, the characterization of NNRTIs and NNIBP may help in the design of more effective drugs that are potent toward wild type and drug-resistant strains of RT. In this paper we attempt to translate the general knowledge gained from a large number of related literature into a set of medicinal chemistry strategies to improve the drug resistance profile of NNRTIs.
Keywords: HIV-1, RT, NNRTIs, drug resistance mutations, drug design
Current Medicinal Chemistry
Title: Design Strategies of Novel NNRTIs to Overcome Drug Resistance
Volume: 16 Issue: 29
Author(s): Peng Zhan, Xinyong Liu, Zhenyu Li, Christophe Pannecouque and Erik De Clercq
Affiliation:
Keywords: HIV-1, RT, NNRTIs, drug resistance mutations, drug design
Abstract: Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are very potent and most promising anti-AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). However, to a great extent, the efficacy of NNRTI drugs is impaired by rapid emergence of drug-resistance mutations. Fortunately, detailed analysis of a wide range of crystal structures of HIV-1 RT/NNRTI complexes together with data on drug resistance mutations has identified factors important for design of inhibitors and resilience to mutations, such as, exhibiting conformational flexibility and positional adaptability of NNRTIs, forming extensive main chain hydrogen bonding, targeting highly conserved residues in HIV-1 RT and possessing unconventional mechanisms for NNRTI-mediated inhibition of RT. Besides, the plasticity of NNRTIs binding pocket (NNIBP) also provides a broad space for the discovery of new generations of NNRTIs. For instance, the composite binding pocket, integrating all available crystal structure information about the NNRTI binding site of HIV RT, was demonstrated to be an effective tool to better understand the flexible nature of the binding pocket and to identify specific inhibitors. The RT/solvent interface proved to be an attractive site for incorporating a moiety to improve water solubility and pharmacokinetics or introducing a second pharmacophore to construct multifunctional ligand. Totally, the characterization of NNRTIs and NNIBP may help in the design of more effective drugs that are potent toward wild type and drug-resistant strains of RT. In this paper we attempt to translate the general knowledge gained from a large number of related literature into a set of medicinal chemistry strategies to improve the drug resistance profile of NNRTIs.
Export Options
About this article
Cite this article as:
Zhan Peng, Liu Xinyong, Li Zhenyu, Pannecouque Christophe and De Clercq Erik, Design Strategies of Novel NNRTIs to Overcome Drug Resistance, Current Medicinal Chemistry 2009; 16 (29) . https://dx.doi.org/10.2174/092986709789178019
DOI https://dx.doi.org/10.2174/092986709789178019 |
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
-
Neprilysin and Amyloid Beta Peptide Degradation
Current Alzheimer Research The ATP-driven Hsp60 Machinery: Biological and Clinical Implications
Current Immunology Reviews (Discontinued) GSK3 at the Edge: Regulation of Developmental Specification and Cell Polarization
Current Drug Targets Early Ischemic Blood Brain Barrier Damage: A Potential Indicator for Hemorrhagic Transformation Following Tissue Plasminogen Activator (tPA) Thrombolysis?
Current Neurovascular Research Recent Approaches for Studying the Role of Glia
CNS & Neurological Disorders - Drug Targets Genetic Variants in Diseases of the Extrapyramidal System
Current Genomics Alpha7 Neuronal Nicotinic Receptors as Targets for Novel Therapies to Treat Multiple Domains of Schizophrenia
Current Pharmaceutical Biotechnology Genes Underlying Monogenic and Multigenic Epilepsies in Mice
Current Genomics Monoamine Oxidase Inhibitors: Ten Years of Docking Studies
Current Topics in Medicinal Chemistry A Closer Look to Polyesters: Properties, Synthesis, Characterization, and Particle Drug Delivery Applications
Nanoscience & Nanotechnology-Asia “European Panel on Low Density Lipoprotein (LDL) Subclasses”: A Statement on the Pathophysiology, Atherogenicity and Clinical Significance of LDL Subclasses
Current Vascular Pharmacology Systemic and Biophase Bioavailability and Pharmacokinetics of Nanoparticulate Drug Delivery Systems
Current Drug Delivery A Translational View of Peptide Treatment of Neurological Disorders
Current Medicinal Chemistry Phenomenology and Neurobiology of Childhood Onset Schizophrenia
Current Psychiatry Reviews Can MDMA Play a Role in the Treatment of Substance Abuse?
Current Drug Abuse Reviews Fibronectin Expression in the Intervertebral Disc of Monkey
Current Stem Cell Research & Therapy The Role of Autophagy on the Survival of Dopamine Neurons
Current Topics in Medicinal Chemistry Frontier View on Nanotechnological Strategies for Neuro-therapy
Current Drug Metabolism Rosuvastatin Induced Rhabdomyolysis in a Low Risk Patient: A Case Report and Review of the Literature
Current Clinical Pharmacology Computational Analysis and Functional Prediction of Ubiquitin Hypothetical Protein: A Possible Target in Parkinson Disease
Central Nervous System Agents in Medicinal Chemistry