Structural and mechanistic bases for a potent HIV-1 capsid inhibitor

doi:10.1126/science.abb4808

GSTDTAP > 气候变化

DOI	10.1126/science.abb4808
	Structural and mechanistic bases for a potent HIV-1 capsid inhibitor
	Stephanie M. Bester; Guochao Wei; Haiyan Zhao; Daniel Adu-Ampratwum; Naseer Iqbal; Valentine V. Courouble; Ashwanth C. Francis; Arun S. Annamalai; Parmit K. Singh; Nikoloz Shkriabai; Peter Van Blerkom; James Morrison; Eric M. Poeschla; Alan N. Engelman; Gregory B. Melikyan; Patrick R. Griffin; James R. Fuchs; Francisco J. Asturias; Mamuka Kvaratskhelia
	2020-10-16
发表期刊	Science
出版年	2020
英文摘要	Current HIV treatments require drugs that must be taken daily, and care would be improved with an effective drug that is long-acting. GS-6207 (Lenacapavir) is a drug developed by Gilead Sciences that shows potential for a 6-month dosing interval and is in phase 2/3 clinical trials. Bester et al. describe structural and biophysical studies that provide a basis for the potent antiviral activity of GS-6207. The HIV capsid is cone shaped, and GS-6207 binds two neighboring capsid subunits and stabilizes the curved capsid. GS-6207 also interferes with capsid binding of cofactors that play a role in viral infection. This insight into GS-6207 activity provides a platform for the rational development of improved long-acting therapies. Science , this issue p. [360][1] 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. [1]: /lookup/doi/10.1126/science.abb4808
领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/299349
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Stephanie M. Bester,Guochao Wei,Haiyan Zhao,et al. Structural and mechanistic bases for a potent HIV-1 capsid inhibitor[J]. Science,2020.
APA	Stephanie M. Bester.,Guochao Wei.,Haiyan Zhao.,Daniel Adu-Ampratwum.,Naseer Iqbal.,...&Mamuka Kvaratskhelia.(2020).Structural and mechanistic bases for a potent HIV-1 capsid inhibitor.Science.
MLA	Stephanie M. Bester,et al."Structural and mechanistic bases for a potent HIV-1 capsid inhibitor".Science (2020).