Open AccessEvidence for distinct mechanisms of small molecule inhibitors of filovirus entry
Author(s) -
Adam Schafer,
Rui Xiong,
Laura Cooper,
Raghad Nowar,
Hyun Lee,
Yangfeng Li,
Benjamin E. Ramirez,
Norton P. Peet,
Michael Caffrey,
Gregory R. J. Thatcher,
Erica Ollmann Saphire,
Han Cheng,
Lijun Rong
Publication year - 2021
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1009312
Subject(s) - ebola virus , ebolavirus , viral entry , small molecule , lysosome , mechanism of action , biology , binding site , drug discovery , microbiology and biotechnology , virology , chemistry , virus , enzyme , biochemistry , in vitro , viral replication
Many small molecules have been identified as entry inhibitors of filoviruses. However, a lack of understanding of the mechanism of action for these molecules limits further their development as anti-filoviral agents. Here we provide evidence that toremifene and other small molecule entry inhibitors have at least three distinctive mechanisms of action and lay the groundwork for future development of anti-filoviral agents. The three mechanisms identified here include: (1) direct binding to the internal fusion loop region of Ebola virus glycoprotein (GP); (2) the HR2 domain is likely the main binding site for Marburg virus GP inhibitors and a secondary binding site for some EBOV GP inhibitors; (3) lysosome trapping of GP inhibitors increases drug exposure in the lysosome and further improves the viral inhibition. Importantly, small molecules targeting different domains on GP are synergistic in inhibiting EBOV entry suggesting these two mechanisms of action are distinct. Our findings provide important mechanistic insights into filovirus entry and rational drug design for future antiviral development.