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

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

PLoS pathogens (2018-09-29)
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
ABSTRACT

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.

MATERIALS
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Brand
Product Description

Avanti
PhotoClick Cholesterol, Hex-5′-ynyl 3β-hydroxy-6-diazirinyl-5α-cholan-24-oate, powder