Evidence for distinct mechanisms of small molecule inhibitors of filovirus entry

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...

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Bibliographic Details
Published in:PLoS pathogens 2021-02, Vol.17 (2), p.e1009312-e1009312
Main Authors: Schafer, Adam, Xiong, Rui, Cooper, Laura, Nowar, Raghad, Lee, Hyun, Li, Yangfeng, Ramirez, Benjamin E, Peet, Norton P, Caffrey, Michael, Thatcher, Gregory R J, Saphire, Erica Ollmann, Cheng, Han, Rong, Lijun
Format: Article
Language:English
Subjects:
Antibodies
Aromatic compounds
Binding
Binding sites
Biology and life sciences
Bioterrorism
Crystal structure
Drug dosages
Ebola virus
Ebolavirus
Engineering and Technology
Fatalities
Glycoproteins
Homology
Infectious diseases
Inhibitors
Marburg disease
Medicine and Health Sciences
Molecular structure
Mutants
Mutation
Nucleotide sequence
Physical Sciences
Research and Analysis Methods
Residues
T shape
Toremifene
Tyrosine
Viral diseases
Viral infections
Viruses
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/JOURNAL.PPAT.1009312