美国科罗拉多大学医学院Mamuka Kvaratskhelia和Francisco J. Asturias研究组合作取得一项新成果。他们揭示了强力HIV-1衣壳抑制剂的结构和机制基础。 相关论文发表在2020年10月16日出版的《科学》杂志上。

他们发现GS-6207通过稳定并因此防止感染细胞中衣壳外壳的功能性解聚来抑制HIV-1。 X射线晶体学，冷冻电镜和氢-氘交换实验表明，GS-6207紧密结合两个相邻的衣壳亚基，并促进了远端的六聚体内部和六聚体之间的相互作用，从而稳定了弯曲的衣壳晶格。

此外，GS-6207干扰衣壳与细胞HIV-1辅因子Nup153和CPSF6的结合，介导病毒核输入并直接整合到染色质的基因富集区域。这些发现阐明了对GS-6207的多峰有效抗病毒活性的结构见解，并为合理开发第二代疗法提供了一种手段。

据介绍，有效的HIV-1衣壳抑制剂GS-6207是长效抗逆转录病毒疗法的主要研究成分。

附：英文原文

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

Author: 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

Issue&Volume: 2020/10/16

Abstract: 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.

DOI: 10.1126/science.abb4808

Source: https://science.sciencemag.org/content/370/6514/360