Screening and Identification of Lassa Virus Entry Inhibitors from an FDA-Approved Drug Library

doi:10.1128/JVI.00954-18

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	Screening and Identification of Lassa Virus Entry Inhibitors from an FDA-Approved Drug Library
	Xiao, Gengfu 1,4; Wang, Wei 1,4; Liu, Yang 4; Zhang, Guangshun 2,3; Wang, Shaobo 1,4,5; Wang, Peilin 1,4; Guo, Jiao 1,4; Cao, Junyuan 1,4; Jia, Xiaoying 1,4; Zhang, Leike 1,4
刊名	JOURNAL OF VIROLOGY
	2018-08-01
卷号	92 期号:16 页码:14
关键词	Lassa virus (LASV) glycoprotein complex (GPC) lacidipine phenothrin membrane fusion
ISSN号	0022-538X
DOI	10.1128/JVI.00954-18
英文摘要	Lassa virus (LASV) belongs to the Mammarenavirus genus (family Arenaviridae) and causes severe hemorrhagic fever in humans. At present, there are no Food and Drug Administration (FDA)-approved drugs or vaccines specific for LASV. Here, high-throughput screening of an FDA-approved drug library was performed against LASV entry by using pseudotype virus bearing LASV envelope glycoprotein (GPC). Two hit compounds, lacidipine and phenothrin, were identified as LASV entry inhibitors in the micromolar range. A mechanistic study revealed that both compounds inhibited LASV entry by blocking low-pH-induced membrane fusion. Accordingly, lacidipine showed virucidal effects on the pseudotype virus of LASV. Adaptive mutant analyses demonstrated that replacement of T40, located in the ectodomain of the stable-signal peptide (SSP), with lysine (K) conferred LASV resistance to lacidipine. Furthermore, lacidipine showed antiviral activity against LASV, the closely related Mopeia virus (MOPV), and the New World arenavirus Guanarito virus (GTOV). Drug-resistant variants indicated that V36M in the ectodomain of the SSP mutant and V436A in the transmembrane domain of the GP2 mutant conferred GTOV resistance to lacidipine, suggesting the interface between SSP and GP2 is the target of lacidipine. This study shows that lacidipine is a candidate for LASV therapy, reinforcing the notion that the SSP-GP2 interface provides an entry-targeted platform for arenavirus inhibitor design. IMPORTANCE Currently, there is no approved therapy to treat Lassa fever; therefore, repurposing of approved drugs will accelerate the development of a therapeutic stratagem. In this study, we screened an FDA-approved library of drugs and identified two compounds, lacidipine and phenothrin, which inhibited Lassa virus entry by blocking low-pH-induced membrane fusion. Additionally, both compounds extended their inhibition against the entry of Guanarito virus, and the viral targets were identified as the SSP-GP2 interface.
资助项目	National Key Research and Development Program of China[2018YFA0507204] ; National Natural Sciences Foundation of China[31670165] ; Open Research Fund Program of CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology ; Open Research Fund Program of Wuhan National Bio-Safety Level 4 Lab of CAS[NBL2017008] ; Open Research Fund Program of the State Key Laboratory of Virology of China[2018IOV001]
WOS研究方向	Virology
语种	英语
出版者	AMER SOC MICROBIOLOGY
WOS记录号	WOS:000440292200042
内容类型	期刊论文
源URL	[http://202.127.146.157/handle/2RYDP1HH/5583]
专题	中国科学院武汉植物园
通讯作者	Wang, Wei
作者单位	1.Univ Chinese Acad Sci, Beijing, Peoples R China 2.Nankai Univ, Coll Pharm, Tianjin, Peoples R China 3.Nankai Univ, State Key Lab Med Chem Biol, Tianjin, Peoples R China 4.Chinese Acad Sci, Wuhan Inst Virol, State Key Lab Virol, Wuhan, Hubei, Peoples R China 5.Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA
推荐引用方式 GB/T 7714	Xiao, Gengfu,Wang, Wei,Liu, Yang,et al. Screening and Identification of Lassa Virus Entry Inhibitors from an FDA-Approved Drug Library[J]. JOURNAL OF VIROLOGY,2018,92(16):14.
APA	Xiao, Gengfu.,Wang, Wei.,Liu, Yang.,Zhang, Guangshun.,Wang, Shaobo.,...&Zhang, Leike.(2018).Screening and Identification of Lassa Virus Entry Inhibitors from an FDA-Approved Drug Library.JOURNAL OF VIROLOGY,92(16),14.
MLA	Xiao, Gengfu,et al."Screening and Identification of Lassa Virus Entry Inhibitors from an FDA-Approved Drug Library".JOURNAL OF VIROLOGY 92.16(2018):14.