Abstract
Multiple combinations of antiretroviral drugs have remarkably improved the treatment of HIV-1 infection. However, life-long treatments and drug resistance are still an open issue that requires continuous efforts for the identification of novel antiviral drugs.
Background: The reverse transcriptase-associated ribonuclease H (RNase H) hydrolyzes the HIV genome to allow synthesizing viral DNA. Currently, no RNase H inhibitors (RHIs) have reached the clinical phase. Therefore, RNase H can be defined as an attractive target for drug design.
Objective: Despite the wealth of information available for RNase H domain, the development of RHIs with high specificity and low cellular toxicity has been disappointing. However, it is now becoming increasingly evident that reverse transcriptase is a highly versatile enzyme, undergoing major structural alterations to complete its catalysis, and that exists a close spatial and temporal interplay between reverse transcriptase polymerase and RNase H domains. This review sums up the present challenges in targeting RNase H encompassing the challenges in selectively inhibiting RNase H vs polymerase and/or HIV-1 integrase and the weak antiviral activity of active site inhibitors, probably for a substrate barrier that impedes small molecules to reach the targeted site. Moreover, the focus is given on the most recent progress in the field of medicinal chemistry that has led to the identification of several small molecules as RHIs in the last few years.
Conclusion: RHIs could be a new class of drugs with a novel mechanism of action highly precious for the treatment of resistant HIV strains.
Keywords: Ribonuclease H, reverse transcriptase, metalloenzyme, RNase H inhibitors, drug design, HIV-1, AIDS, antiviral.
Current Medicinal Chemistry
Title:Small-molecule Inhibitors of HIV-1 Reverse Transcriptase-Associated Ribonuclease H Function: Challenges and Recent Developments
Volume: 28 Issue: 30
Author(s): Valentina Noemi Madia, Antonella Messore, Alessandro De Leo, Valeria Tudino, Ivano Pindinello, Francesco Saccoliti, Daniela De Vita, Luigi Scipione, Roberta Costi*Roberto Di Santo
Affiliation:
- Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur - Fondazione Cenci Bolognetti, “Sapienza” Università di Roma, p.le Aldo Moro 5, I-00185 Rome,Italy
Keywords: Ribonuclease H, reverse transcriptase, metalloenzyme, RNase H inhibitors, drug design, HIV-1, AIDS, antiviral.
Abstract:
Multiple combinations of antiretroviral drugs have remarkably improved the treatment of HIV-1 infection. However, life-long treatments and drug resistance are still an open issue that requires continuous efforts for the identification of novel antiviral drugs.
Background: The reverse transcriptase-associated ribonuclease H (RNase H) hydrolyzes the HIV genome to allow synthesizing viral DNA. Currently, no RNase H inhibitors (RHIs) have reached the clinical phase. Therefore, RNase H can be defined as an attractive target for drug design.
Objective: Despite the wealth of information available for RNase H domain, the development of RHIs with high specificity and low cellular toxicity has been disappointing. However, it is now becoming increasingly evident that reverse transcriptase is a highly versatile enzyme, undergoing major structural alterations to complete its catalysis, and that exists a close spatial and temporal interplay between reverse transcriptase polymerase and RNase H domains. This review sums up the present challenges in targeting RNase H encompassing the challenges in selectively inhibiting RNase H vs polymerase and/or HIV-1 integrase and the weak antiviral activity of active site inhibitors, probably for a substrate barrier that impedes small molecules to reach the targeted site. Moreover, the focus is given on the most recent progress in the field of medicinal chemistry that has led to the identification of several small molecules as RHIs in the last few years.
Conclusion: RHIs could be a new class of drugs with a novel mechanism of action highly precious for the treatment of resistant HIV strains.
Export Options
About this article
Cite this article as:
Madia Noemi Valentina , Messore Antonella , De Leo Alessandro , Tudino Valeria , Pindinello Ivano , Saccoliti Francesco , De Vita Daniela , Scipione Luigi , Costi Roberta *, Di Santo Roberto, Small-molecule Inhibitors of HIV-1 Reverse Transcriptase-Associated Ribonuclease H Function: Challenges and Recent Developments, Current Medicinal Chemistry 2021; 28 (30) . https://dx.doi.org/10.2174/0929867328666210322164557
DOI https://dx.doi.org/10.2174/0929867328666210322164557 |
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
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
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
An Overview of Drug Screening Using Primary and Embryonic Stem Cells
Combinatorial Chemistry & High Throughput Screening Optic Nerve and Cerebral Edema in the Course of Diabetic Ketoacidosis
Current Neuropharmacology Pharmacological Activities and Therapeutic Potential of Kaempferitrin in Medicine for the Treatment of Human Disorders: A Review of Medicinal Importance and Health Benefits
Cardiovascular & Hematological Disorders-Drug Targets QSARs, Data and Error in the Modern Age of Drug Discovery
Current Topics in Medicinal Chemistry Novel Aspects of Natural and Modified Vinca Alkaloids
Current Medicinal Chemistry - Anti-Cancer Agents Targeting Cardiomyocyte Ca<sup>2+</sup> Homeostasis in Heart Failure
Current Pharmaceutical Design Plant Natural Products in Anticancer Drug Discovery
Current Organic Chemistry The Therapeutic use of the Zonulin Inhibitor AT-1001 (Larazotide) for a Variety of Acute and Chronic Inflammatory Diseases
Current Medicinal Chemistry A Review of Natural and Modified Betulinic, Ursolic and Echinocystic Acid Derivatives as Potential Antitumor and Anti-HIV Agents
Mini-Reviews in Medicinal Chemistry Lipid Metabolism and Nutrient Partitioning Strategies
Current Drug Targets - CNS & Neurological Disorders Synthesis and Biological Evaluation of 2-thiazolylimino-5-arylidene-4- thiazolidinone Derivatives as Potent Antimycobacterial Agents
Anti-Infective Agents Adenosine and Adenosine Receptors in the Pathomechanism and Treatment of Respiratory Diseases
Current Medicinal Chemistry New Approaches for the Treatment of Allergic Conditions
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Black Tea Polyphenols-Mediated In Vivo Cellular Responses During Carcinogenesis
Mini-Reviews in Medicinal Chemistry Conservation of Hydrophobicity within Viral Envelope Glycoproteins Reveals a Putative Hepatitis C Virus Fusion Peptide
Protein & Peptide Letters Integration of Physicochemical and Pharmacokinetic Parameters in Lead Optimization: A Physiological Pharmacokinetic Model Based Approach
Current Drug Discovery Technologies Cannabinoid Receptors as Therapeutic Targets
Current Pharmaceutical Design Psychiatric Rehabilitation Pertaining to Health Care Environments: Facilitating Skills and Supports of People with Mental Illness in Relation to their Mental and Physical Health Care
Current Psychiatry Reviews Molecular Aspects of the RT/drug Interactions. Perspective of Dual Inhibitors
Current Pharmaceutical Design Nucleoside Inhibitors of Hepatitis C Virus NS5B Polymerase: A Systematic Review
Current Drug Targets