摘要
Dear Editor,Lassa virus(LASV)belongs to the Mammarenavirus genus,Arenaviridae family.Arenaviruses are classified into two main groups-Old World(OW)and New World(NW)-based on virus genetics,serology,antigenic properties and geographical relationships.The 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)agents.The 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 ST-161.As a result,21 derivatives with IC50 values<1 pmol/L are presented in Table S1.Hit 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 investigated.To 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).
