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Bester, Stephanie M; Wei, Guochao; Zhao, Haiyan; Adu-Ampratwum, Daniel; Iqbal, Naseer; Courouble, Valentine V; Francis, Ashwanth C; Annamalai, Arun S; Singh, Parmit K; Shkriabai, Nikoloz; Van Blerkom, Peter; Morrison, James; Poeschla, Eric M; Engelman, Alan N; Melikyan, Gregory B; Griffin, Patrick R; Fuchs, James R; Asturias, Francisco J; Kvaratskhelia, Mamuka
Science (American Association for the Advancement of Science), 10/2020, Letnik: 370, Številka: 6514Journal Article
The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing functional disassembly of the capsid shell in infected cells. X-ray crystallography, cryo-electron microscopy, and hydrogen-deuterium exchange experiments revealed that GS-6207 tightly binds two adjoining capsid subunits and promotes distal intra- and inter-hexamer interactions that stabilize the curved capsid lattice. In addition, GS-6207 interferes with capsid binding to the cellular HIV-1 cofactors Nup153 and CPSF6 that mediate viral nuclear import and direct integration into gene-rich regions of chromatin. These findings elucidate structural insights into the multimodal, potent antiviral activity of GS-6207 and provide a means for rationally developing second-generation therapies.
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in: SICRIS
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