HIV-1 gp120 Antagonists Also Inhibit HIV-1 Reverse Transcriptase by Bridging the NNRTI and NRTI Sites.
Allosteric Regulation
Anti-HIV Agents
/ chemistry
Binding Sites
Cell Line
Crystallography, X-Ray
HIV Envelope Protein gp120
/ antagonists & inhibitors
HIV Reverse Transcriptase
/ antagonists & inhibitors
HIV-1
/ drug effects
Humans
Molecular Docking Simulation
Molecular Structure
Reverse Transcriptase Inhibitors
/ chemistry
Structure-Activity Relationship
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
25 11 2021
25 11 2021
Historique:
pubmed:
5
11
2021
medline:
29
1
2022
entrez:
4
11
2021
Statut:
ppublish
Résumé
HIV-1 infection is typically treated using ≥2 drugs, including at least one HIV-1 reverse transcriptase (RT) inhibitor. Drugs targeting RT comprise nucleos(t)ide RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). NRTI-triphosphates bind at the polymerase active site and, following incorporation, inhibit DNA elongation. NNRTIs bind at an allosteric pocket ∼10 Å away from the polymerase active site. This study focuses on compounds ("NBD derivatives") originally developed to bind to HIV-1 gp120, some of which inhibit RT. We have determined crystal structures of three NBD compounds in complex with HIV-1 RT, correlating with RT enzyme inhibition and antiviral activity, to develop structure-activity relationships. Intriguingly, these compounds bridge the dNTP and NNRTI-binding sites and inhibit the polymerase activity of RT in the enzymatic assays (IC
Identifiants
pubmed: 34735153
doi: 10.1021/acs.jmedchem.1c01104
pmc: PMC10655131
mid: NIHMS1941657
doi:
Substances chimiques
Anti-HIV Agents
0
HIV Envelope Protein gp120
0
Reverse Transcriptase Inhibitors
0
reverse transcriptase, Human immunodeficiency virus 1
EC 2.7.7.-
HIV Reverse Transcriptase
EC 2.7.7.49
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
16530-16540Subventions
Organisme : NIAID NIH HHS
ID : R01 AI027690
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI104416
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI104416
Pays : United States
Commentaires et corrections
Type : ErratumIn
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