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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.
Filoviruses are among the deadliest pathogens known to mankind with case-fatality rates ranging from 25–90%. New outbreaks in central Africa and the identification of novel filoviruses in other regions highlight the urgent need to develop novel therapeutics. Although many novel anti-filovirus compounds have been reported as entry inhibitors, to date, none have made to market. This high rate of failure is in part due to a lack of knowledge of the mechanisms of action. In this report, we provide a molecular basis for the multiple mechanisms of action by which small molecule inhibitors of Ebola virus and Marburg virus block virus entry, which provides new mechanistic insight to guide design for next-generation viral entry inhibitors.