Structure-activity relationship optimization for lassa virus fusion inhibitors targeting the transmembrane domain of GP2

作     者：Guangshun Zhang Junyuan Cao Yan Cai Yang Liu Yanli Li Peilin Wang Xiaoying Jia Mengmeng Zhang Gengfu Xiao Yu Guo Wei Wang 

作者机构：State Key Laboratory of VirologyWuhan Institute of VirologyChinese Academy of SciencesWuhan 430071China College of Pharmacy and State Key Laboratory of Medicinal Chemical BiologyNankai UniversityTianjin 300450China University of the Chinese Academy of SciencesBeijing 100049China Drug Discovery Center for Infectious DiseaseNankai UniversityTianjin 300071China Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjin 300450China 

出 版 物：《Protein & Cell》 (蛋白质与细胞（英文版）)

年 卷 期：2019年第10卷第2期

页      面：137-142页

核心收录：

学科分类：0710[理学-生物学] 07[理学] 09[农学] 

基　　金：supported by the National Key Research and Development Program of China 国家自然科学基金 the Open Research Fund Program of CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology the Open Research Fund Program of Wuhan National Bio-Safety Level 4 Lab of CAS the Open Research Fund Program of the State Key Laboratory of Virology of China 

主　　题：Editor World MACV 

摘      要：Dear Editor,Lassa virus(LASV)belongs to the Mammarenavirus genus,Arenaviridae *** are classified into two main groups-Old World(OW)and New World(NW)-based on virus genetics,serology,antigenic properties and geographical *** OW LASV and Lujo virus(LUJV),as well as NW Jurn n virus(JUNV),Machupo virus(MACV),Guanarito virus(GTOV),Sabia virus(SABV)and Chapare virus(CHAPV),are known to cause severe hemorrhagic fever and are listed as biosafety level 4(BSL-4)*** arenavirus glycoprotein complex(GPC)contains three subunits-the retained stable-signal peptide(SSP),the receptor-binding subunit GP1,and the membrane fusion subunit GP2(Lenz et al.,2001).Notably,the proximate external membrane region and TM of GP2,together with the ectodomain loop and TMs of SSP,form an SSP-GP2 interface,playing essential roles in regulating membrane fusion,and providing targets for distinct fusion inhibitors(Larson et al.,2008;Lee et al.,2008;York et al.,2008;York and Nunberg,2009;Thomas et al.,2011;Burgeson et al.,2013a;Shankar et al.,2016;Wang et al.,2016;Wang et al.,2018).Among these inhibitors,ST-161 is LASV specific(Burgeson et al.,2013a).In this study,we conducted structure-activity relationship(SAR)optimization of *** a result,21 derivatives with IC50 values1 pmol/L are presented in Table *** compounds 21,29 and 57 exhibiting robust inhibition of the LASV pseudotype virus(LASVpv,VSV backbone enveloped by LASV GPC with single cycle infection)entry with IC50 values lower than 0.2 nmol/L(Figs.1A and S1),as well as hit compound 72 with an ester bond instead of acylhydrazone,were further *** test whether the four hit compounds inhibit LASV entry by blocking the GPC-mediated membrane fusion,the inhibition effects of these compounds against LASV GPC mediated fusion were quantitatively determined by dual-luciferase assay(Thomas et al.,2011;Wang et al.,2018).