Critical role for cholesterol in Lassa fever virus entry identified by a novel small molecule inhibitor targeting the viral receptor LAMP1.

Autor: May Kwang-Mei Wang, Tao Ren, Hu Liu, Sun-Young Lim, Kyungae Lee, Anna Honko, Huanying Zhou, Julie Dyall, Lisa Hensley, Ashley K Gartin, James M Cunningham
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: PLoS Pathogens, Vol 14, Iss 9, p e1007322 (2018)
Druh dokumentu: article
ISSN: 1553-7366
1553-7374
DOI: 10.1371/journal.ppat.1007322
Popis: Lassa fever virus (LASV) is endemic in West Africa and causes severe hemorrhagic fever and sensorineural hearing loss. We identified a small molecule inhibitor of LASV and used it to analyze the mechanism of entry. Using a photo-reactive analog that retains antiviral activity as a probe, we identified the inhibitor target as lysosome-associated membrane protein 1 (LAMP1), a host factor that binds to the LASV glycoprotein (GP) during infection. We found that LAMP1 binding to LASV GP is cholesterol-dependent, and that the inhibitor blocks infection by competing with cholesterol in LAMP1. Mutational analysis of a docking-based model identified a putative inhibitor binding site in the cholesterol-binding pocket within the LAMP1 domain that binds GP. These findings identify a critical role for cholesterol in LASV entry and a potential target for therapeutic intervention.
Databáze: Directory of Open Access Journals
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