{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Losada N"],"funding":["National Institute of Allergy and Infectious Diseases","NIAID NIH HHS"],"pagination":["16530-16540"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10655131"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["64(22)"],"pubmed_abstract":["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<sub>50</sub> < 5 μM). Two of the lead compounds, NBD-14189 and NBD-14270, show potent antiviral activity (EC<sub>50</sub> < 200 nM), and NBD-14270 shows low cytotoxicity (CC<sub>50</sub> > 100 μM)."],"journal":["Journal of medicinal chemistry"],"pubmed_title":["HIV-1 gp120 Antagonists Also Inhibit HIV-1 Reverse Transcriptase by Bridging the NNRTI and NRTI Sites."],"pmcid":["PMC10655131"],"funding_grant_id":["R01 AI027690","R01 AI104416"],"pubmed_authors":["Curreli F","Gruber K","Pilch A","Debnath AK","Arnold E","Ruiz FX","Losada N","Das K"],"additional_accession":[]},"is_claimable":false,"name":"HIV-1 gp120 Antagonists Also Inhibit HIV-1 Reverse Transcriptase by Bridging the NNRTI and NRTI Sites.","description":"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<sub>50</sub> < 5 μM). Two of the lead compounds, NBD-14189 and NBD-14270, show potent antiviral activity (EC<sub>50</sub> < 200 nM), and NBD-14270 shows low cytotoxicity (CC<sub>50</sub> > 100 μM).","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Nov","modification":"2024-10-15T17:42:43.817Z","creation":"2024-10-15T17:42:43.817Z"},"accession":"S-EPMC10655131","cross_references":{"pubmed":["34735153"],"doi":["10.1021/acs.jmedchem.1c01104"]}}