Abstract
We recently described that the chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(β-Dribofuranosyl) quinoline-3-carboxylic acid (compound A) inhibits the human immunodeficiency virus type 1 (HIV-1) enzyme reverse transcriptase (RT), and its replication in primary cells. Based on these findings, we performed kinetic studies to investigate the mode of inhibition of compound A and its aglycan analog (compound B). We found that both molecules inhibited RT activity independently of the template/primer used. Nevertheless, compound A was 10-fold more potent than compound B. Compound A inhibited the RNA-dependent DNA polymerase (RDDP) activity of RT with an uncompetitive and a noncompetitive mode of action with respect to dTTP incorporation and to template/primer (TP) uptake, respectively. The kinetic pattern of the inhibition displayed by compound A was probably due to its greater affinity for the ternary complex (RT-TP-dNTP) than the enzyme alone or the binary complex (RT-TP). Besides, by means of molecular modeling, we show that compound A bound on the NNRTI binding pocket of RT. However, our molecule targets such a site by making novel interactions with the enzyme RT, when compared to NNRTIs. These include a hydrogen bridge between the 2-OH of our compound and the Tyr675 of the enzyme RTs chain B. Therefore, compound A is able to synergize with both a NRTI (AZT-TP) and a NNRTI (efavirenz). Taken together, our results suggest that compound A displays a novel mechanism of action, which may be different from classical NRTIs and NNRTIs.
Keywords: AIDS, HIV-1, Reverse transcriptase, Chloroxoquinolinic acid
Current HIV Research
Title: Characterization of HIV-1 Enzyme Reverse Transcriptase Inhibition by the Compound 6-Chloro-1,4-Dihydro-4-Oxo-1-(β-D-Ribofuranosyl) Quinoline-3-Carboxylic Acid Through Kinetic and In Silico Studies
Volume: 7 Issue: 3
Author(s): Thiago Moreno L. Souza, Diego Q. Rodrigues, Vitor F. Ferreira, Isakelly Pereira Marques, Fernanda da Costa Santos, Anna Claudia Cunha, Maria Cecilia Bastos Vieira de Souza, Izabel Christina de Palmer Paixao Frugulhetti, Dumith Chequer Bou-Habib and Carlos Frederico Leite Fontes
Affiliation:
Keywords: AIDS, HIV-1, Reverse transcriptase, Chloroxoquinolinic acid
Abstract: We recently described that the chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(β-Dribofuranosyl) quinoline-3-carboxylic acid (compound A) inhibits the human immunodeficiency virus type 1 (HIV-1) enzyme reverse transcriptase (RT), and its replication in primary cells. Based on these findings, we performed kinetic studies to investigate the mode of inhibition of compound A and its aglycan analog (compound B). We found that both molecules inhibited RT activity independently of the template/primer used. Nevertheless, compound A was 10-fold more potent than compound B. Compound A inhibited the RNA-dependent DNA polymerase (RDDP) activity of RT with an uncompetitive and a noncompetitive mode of action with respect to dTTP incorporation and to template/primer (TP) uptake, respectively. The kinetic pattern of the inhibition displayed by compound A was probably due to its greater affinity for the ternary complex (RT-TP-dNTP) than the enzyme alone or the binary complex (RT-TP). Besides, by means of molecular modeling, we show that compound A bound on the NNRTI binding pocket of RT. However, our molecule targets such a site by making novel interactions with the enzyme RT, when compared to NNRTIs. These include a hydrogen bridge between the 2-OH of our compound and the Tyr675 of the enzyme RTs chain B. Therefore, compound A is able to synergize with both a NRTI (AZT-TP) and a NNRTI (efavirenz). Taken together, our results suggest that compound A displays a novel mechanism of action, which may be different from classical NRTIs and NNRTIs.
Export Options
About this article
Cite this article as:
Souza L. Thiago Moreno, Rodrigues Q. Diego, Ferreira F. Vitor, Marques Pereira Isakelly, Santos da Costa Fernanda, Cunha Claudia Anna, de Souza Bastos Vieira Maria Cecilia, Paixao Frugulhetti de Palmer Izabel Christina, Bou-Habib Chequer Dumith and Fontes Frederico Leite Carlos, Characterization of HIV-1 Enzyme Reverse Transcriptase Inhibition by the Compound 6-Chloro-1,4-Dihydro-4-Oxo-1-(β-D-Ribofuranosyl) Quinoline-3-Carboxylic Acid Through Kinetic and In Silico Studies, Current HIV Research 2009; 7 (3) . https://dx.doi.org/10.2174/157016209788347958
DOI https://dx.doi.org/10.2174/157016209788347958 |
Print ISSN 1570-162X |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4251 |
Call for Papers in Thematic Issues
Management of HIV: Management of HIV: old challenges and new needs
The aim of this thematic issue is to provide the most recent updates regarding the effective management of HIV infection. Antiretroviral therapy (ART) has significantly decreased HIV-related mortality, leading to an enhancement in the quality of life and life expectancy for people living with HIV (PLWH). Despite the numerous advancements ...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
Related Articles
-
Evaluation of Substituted Benzaldehydes Against Mycobacterium tuberculosis
Letters in Drug Design & Discovery Therapeutic Options for the Treatment of 2019-Novel Coronavirus in India: A Review
Coronaviruses Treatment of Insomnia, Insomnia Symptoms, and Obstructive Sleep Apnea During and After Menopause: Therapeutic Approaches
Current Psychiatry Reviews Glucocorticoids and the Cardiovascular System: State of the Art
Current Pharmaceutical Design Parkinson's Disease Management. Part II- Discovery of MAO-B Inhibitors Based on Nitrogen Heterocycles and Analogues
Current Topics in Medicinal Chemistry Can Enzyme Engineering Benefit from the Modulation of Protein Motions? Lessons Learned from NMR Relaxation Dispersion Experiments
Protein & Peptide Letters Metabolism-based Drug-drug Interactions in Patients with Chronic Respiratory Diseases: A Review Focusing on Drugs Affecting the Respiratory System
Current Drug Metabolism Radar Cross Section Identification of Air Targets using the Cosine Transform and Neural Networks
Recent Patents on Engineering Plant MicroRNA Potential in Targeting Sars-CoV-2 Genome Offering Efficient Antiviral MiRNA-Based Therapies
MicroRNA Focused Microarray Analysis: Characterization of Phenomes by Gene Expression Profiling
Current Pharmacogenomics A Chronic Inflammatory Inductive Condition in the Nursing Profession: A Scoping Review
Endocrine, Metabolic & Immune Disorders - Drug Targets Phenylbenzopyrone of Flavonoids as a Potential Scaffold to Prevent SARSCoV-2 Replication by Inhibiting its M<sup>PRO</sup> Main Protease
Current Pharmaceutical Biotechnology Cytokine Storm and Immunomodulation in COVID-19: A Review
Coronaviruses Assessment of Stress, Anxiety, and Depression Levels Among COVID-19 Positive Patients Admitted in Rural Tertiary Care Hospital
Coronaviruses 1950 MHz Electromagnetic Fields Ameliorate Aβ Pathology in Alzheimer’s Disease Mice
Current Alzheimer Research The hERG Channel and Risk of Drug-Acquired Cardiac Arrhythmia: An Overview
Current Topics in Medicinal Chemistry Novel dibenzo[b,d]furan–1H-1,2,4-triazole derivatives: Synthesis and antitumor activity
Anti-Cancer Agents in Medicinal Chemistry Roles of Secreted Phospholipases A<sub>2</sub> in the Mammalian Immune System
Protein & Peptide Letters Millennium Nutrient N,N-Dimethylglycine (DMG) and its Effectiveness in Autism Spectrum Disorders
Current Medicinal Chemistry Current Progress in Antifibroitcs
Current Medicinal Chemistry