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HIV-1 gp120 Antagonists Also Inhibit HIV-1 Reverse Transcriptase by Bridging the NNRTI and NRTI Sitesстатья
Статья опубликована в высокорейтинговом журнале
Статья опубликована в журнале из списка Web of Science и/или ScopusДата последнего поиска статьи во внешних источниках: 22 декабря 2021 г.
- Авторы: Losada Natalie, Ruiz Francesc X., Curreli Francesca, Gruber Kevin, Pilch Alyssa, Altieri Andrea, Kurkin Alexander V., Das Kalyan, Debnath Asim K., Arnold Eddy
- Журнал: Journal of Medicinal Chemistry
- Том: 64
- Номер: 22
- Год издания: 2021
- Издательство: American Chemical Society
- Местоположение издательства: United States
- Первая страница: 16530
- Последняя страница: 16540
- DOI: 10.1021/acs.jmedchem.1c02061
- Аннотация: 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 (IC50 < 5 μM). Two of the lead compounds, NBD-14189 and NBD-14270, show potent antiviral activity (EC50 < 200 nM), and NBD-14270 shows low cytotoxicity (CC50 > 100 μM).
- Добавил в систему: Куркин Александр Витальевич