7SLR

HIV Reverse Transcriptase with compound Pyr01

Summary for 7SLR

• Entry DOI: 10.2210/pdb7slr/pdb
• Descriptor: Reverse transcriptase/ribonuclease H, 5-(difluoromethyl)-3-({1-[(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl}oxy)-2-methylbenzonitrile (3 entities in total)
• Functional Keywords: hiv, reverse transcriptase, rt, nnrti, viral protein
• Biological source: Human immunodeficiency virus type 1 (HIV-1)
• Total number of polymer chains: 2
• Total formula weight: 129890.63

Authors

Klein, D.J.,Zebisch, M.,Gu, M. (deposition date: 2021-10-24, release date: 2022-11-23, Last modification date: 2024-05-22)

Primary citation

Balibar, C.J.,Klein, D.J.,Zamlynny, B.,Diamond, T.L.,Fang, Z.,Cheney, C.A.,Kristoff, J.,Lu, M.,Bukhtiyarova, M.,Ou, Y.,Xu, M.,Ba, L.,Carroll, S.S.,El Marrouni, A.,Fay, J.F.,Forster, A.,Goh, S.L.,Gu, M.,Krosky, D.,Rosenbloom, D.I.S.,Sheth, P.,Wang, D.,Wu, G.,Zebisch, M.,Zhao, T.,Zuck, P.,Grobler, J.,Hazuda, D.J.,Howell, B.J.,Converso, A.
Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1.
Sci Transl Med, 15:eabn2038-eabn2038, 2023

PubMed Abstract: Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside reverse transcriptase inhibitors induce HIV-1 selective cytotoxicity in vitro but require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1-infected cell kill potency at clinically achievable concentrations. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1 cell death through premature intracellular viral protease activation. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4 T cells isolated from people living with HIV-1, supporting an immune-independent clearance strategy.

PubMed: 36812345
DOI: 10.1126/scitranslmed.abn2038

Experimental method

X-RAY DIFFRACTION (2.179 Å)