Screening and Identification of Lassa Virus Entry Inhibitors from a Fragment-Based Drug Discovery Library

Yuxia Hou; Yang Liu; Xiaoying Jia; Minmin Zhou; Wenting Mao; Siqi Dong; Yueli Zhang; Gengfu Xiao; Wei Wang

doi:10.3390/v14122649

Screening and Identification of Lassa Virus Entry Inhibitors from a Fragment-Based Drug Discovery Library

Viruses. 2022 Nov 27;14(12):2649. doi: 10.3390/v14122649.

Authors

Yuxia Hou^{1

2}, Yang Liu¹, Xiaoying Jia^{1

2}, Minmin Zhou^{1

2}, Wenting Mao^{1

2}, Siqi Dong^{1

2}, Yueli Zhang^{1

3}, Gengfu Xiao^{1

2}, Wei Wang^{1

2}

Affiliations

¹ State Key Laboratory of Virology, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
² University of the Chinese Academy of Sciences, Beijing 100049, China.
³ State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, China.

Abstract

Lassa virus (LASV) is a highly pathogenic virus that is categorized as a biosafety level-4 pathogen. Currently, there are no approved drugs or vaccines specific to LASV. In this study, high-throughput screening of a fragment-based drug discovery library was performed against LASV entry using a pseudotype virus bearing the LASV envelope glycoprotein complex (GPC). Two compounds, F1920 and F1965, were identified as LASV entry inhibitors that block GPC-mediated membrane fusion. Analysis of adaptive mutants demonstrated that the transient mutants L442F and I445S, as well as the constant mutant F446L, were located on the same side on the transmembrane domain of the subunit GP2 of GPC, and all the mutants conferred resistance to both F1920 and F1965. Furthermore, F1920 antiviral activity extended to other highly pathogenic mammarenaviruses, whereas F1965 was LASV-specific. Our study showed that both F1920 and F1965 provide a potential backbone for the development of lead drugs for preventing LASV infection.

Keywords: Lassa virus (LASV); fragment-based drug discovery (FBDD) library; glycoprotein complex (GPC); membrane fusion; transmembrane domain (TM).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / pharmacology
Antiviral Agents / therapeutic use
Arenaviridae*
Drug Discovery
HIV Fusion Inhibitors* / therapeutic use
Humans
Lassa Fever*
Lassa virus

Substances

Antiviral Agents
HIV Fusion Inhibitors

Grants and funding

This work was supported by the National Key Research and Development Program of China (2018YFA0507204), the National Natural Sciences Foundation of China (82172273 and 31670165), Wuhan National Biosafety Laboratory, Chinese Academy of Sciences Advanced Customer Cultivation Project (2019ACCP-MS03), and the Open Research Fund Program of the State Key Laboratory of Virology of China (2018IOV001).