Abstract
Human immunodeficiency virus (HIV) remains a global health problem. While combined antiretroviral therapy has been successful in controlling the virus in patients, HIV can develop resistance to drugs used for treatment, rendering available drugs less effective and limiting treatment options. Initiatives to find novel drugs for HIV treatment are ongoing, although traditional drug design approaches often focus on known binding sites for inhibition of established drug targets like reverse transcriptase and integrase. These approaches tend towards generating more inhibitors in the same drug classes already used in the clinic. Lack of diversity in antiretroviral drug classes can result in limited treatment options, as cross-resistance can emerge to a whole drug class in patients treated with only one drug from that class. A fresh approach in the search for new HIV-1 drugs is fragment-based drug discovery (FBDD), a validated strategy for drug discovery based on using smaller libraries of low molecular weight molecules (<300 Da) screened using primarily biophysical assays. FBDD is aimed at not only finding novel drug scaffolds, but also probing the target protein to find new, often allosteric, inhibitory binding sites. Several fragment-based strategies have been successful in identifying novel inhibitory sites or scaffolds for two proven drug targets for HIV-1, reverse transcriptase and integrase. While any FBDD-generated HIV-1 drugs have yet to enter the clinic, recent FBDD initiatives against these two well-characterised HIV-1 targets have reinvigorated antiretroviral drug discovery and the search for novel classes of HIV-1 drugs.
Keywords: Antiretrovirals, HIV-1, Fragment-based drug discovery, Reverse transcriptase, Integrase, Fragment screening.
Current Topics in Medicinal Chemistry
Title:Fragment Based Strategies for Discovery of Novel HIV-1 Reverse Transcriptase and Integrase Inhibitors
Volume: 16 Issue: 10
Author(s): Catherine F. Latham, Jennifer La, Ricky N. Tinetti, David K. Chalmers and Gilda Tachedjian
Affiliation:
Keywords: Antiretrovirals, HIV-1, Fragment-based drug discovery, Reverse transcriptase, Integrase, Fragment screening.
Abstract: Human immunodeficiency virus (HIV) remains a global health problem. While combined antiretroviral therapy has been successful in controlling the virus in patients, HIV can develop resistance to drugs used for treatment, rendering available drugs less effective and limiting treatment options. Initiatives to find novel drugs for HIV treatment are ongoing, although traditional drug design approaches often focus on known binding sites for inhibition of established drug targets like reverse transcriptase and integrase. These approaches tend towards generating more inhibitors in the same drug classes already used in the clinic. Lack of diversity in antiretroviral drug classes can result in limited treatment options, as cross-resistance can emerge to a whole drug class in patients treated with only one drug from that class. A fresh approach in the search for new HIV-1 drugs is fragment-based drug discovery (FBDD), a validated strategy for drug discovery based on using smaller libraries of low molecular weight molecules (<300 Da) screened using primarily biophysical assays. FBDD is aimed at not only finding novel drug scaffolds, but also probing the target protein to find new, often allosteric, inhibitory binding sites. Several fragment-based strategies have been successful in identifying novel inhibitory sites or scaffolds for two proven drug targets for HIV-1, reverse transcriptase and integrase. While any FBDD-generated HIV-1 drugs have yet to enter the clinic, recent FBDD initiatives against these two well-characterised HIV-1 targets have reinvigorated antiretroviral drug discovery and the search for novel classes of HIV-1 drugs.
Export Options
About this article
Cite this article as:
Latham F. Catherine, La Jennifer, Tinetti N. Ricky, Chalmers K. David and Tachedjian Gilda, Fragment Based Strategies for Discovery of Novel HIV-1 Reverse Transcriptase and Integrase Inhibitors, Current Topics in Medicinal Chemistry 2016; 16 (10) . https://dx.doi.org/10.2174/1568026615666150901114329
DOI https://dx.doi.org/10.2174/1568026615666150901114329 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
-
Therapeutic Application of Natural Medicine Monomers in Cancer Treatment
Current Medicinal Chemistry Serum miRNAs Signature Plays an Important Role in Keloid Disease
Current Molecular Medicine Peptide-Mediated Delivery of Therapeutic and Imaging Agents Into Mammalian Cells
Current Pharmaceutical Design Preclinical and Clinical Studies of Novel Breast Cancer Drugs Targeting Molecules Involved in Protein Kinase C Signaling, the Putative Metastasis-Suppressor Gene Cap43 and the Y-box Binding Protein-1
Current Medicinal Chemistry Omega-3 Fatty Acid Treatment Combined with Chemotherapy to Prevent Toxicity, Drug Resistance, and Metastasis in Cancer
Current Drug Targets Peptides for Diagnosis and Treatment of Colorectal Cancer
Current Medicinal Chemistry Insights into the Role of mTOR/AMPK as a Potential Target for Anticancer Therapy
Current Drug Therapy Glycosidated Phospholipids – a Promising Group of Anti-Tumour Lipids
Anti-Cancer Agents in Medicinal Chemistry Editorial (Thematic Issue: Targeting Mammalian Spermatogenesis: A Matter of Support)
Current Molecular Pharmacology Role of NF-κB in the Regulation of Cytochrome P450 Enzymes
Current Drug Metabolism Near-Infrared Dyes: Probe Development and Applications in Optical Molecular Imaging
Current Organic Synthesis Prolyl Oligopeptidase, Inositol Phosphate Signalling and Lithium Sensitivity
CNS & Neurological Disorders - Drug Targets Herbal Phytochemicals as Immunomodulators
Current Immunology Reviews (Discontinued) Metallodrugs in Targeted Cancer Therapeutics: Aiming at Chemoresistance- related Patterns and Immunosuppressive Tumor Networks
Current Medicinal Chemistry Functional Link between BRCA1 and BAP1 through Histone H2A, Heterochromatin and DNA Damage Response
Current Cancer Drug Targets Role of Azoles in Cancer Prevention and Treatment: Present and Future Perspectives
Anti-Cancer Agents in Medicinal Chemistry Patent Annotations
Recent Patents on Anti-Infective Drug Discovery Methanobrevibacter smithii Archaeosomes-Entrapped mzNL4-3 Virus-Like Particles Induce Specific T helper 1-Oriented Cellular and Humoral Responses Against HIV-1
Current HIV Research MicroRNAs in Breast Cancer: One More Turn in Regulation
Current Drug Targets Anti-Genes: siRNA, Ribozymes and Antisense
Current Pharmaceutical Biotechnology