Small molecule inhibitors of Ebola virus entry
Background: Human cells that are susceptible to infection by pathogenic viruses express surface membrane proteins that mediate attachment and membrane fusion activity of virus glycoproteins. There are strong structural and functional similarities among HIV, influenza, Ebola, Lassa fever, respiratory syncytial virus and possibly dengue and hepatitis C virus glycoproteins.
Identification of host proteins of interest: The long standing interest of this laboratory is to identify host proteins that activate virus glycoproteins. Recently, we have focused on the Ebola virus (EboV), which causes outbreaks of rapidly fatal hemorrhagic fever for which there is no therapy. We determined that cleavage of the GP1 subunit of the EboV glycoprotein by host endosomal cysteine proteases is the first step in a two-step mechanism and is functionally analogous to the role of CD4 binding to gp120 in HIV infection.
Small molecule inhibitors of Ebola: In newly completed work, we screened a small molecule library provided by NSRB and identified six novel compounds that inhibit the second, post-protease, step in EboV infection. Four of these compounds specifically inhibit EboV and not Lassa fever or vesicular stomatitis virus (VSV-G) infection. Remarkably, we find that 3.3, a derivative of the EboV inhibitor 3.0, is a more potent inhibitor of the Lassa fever virus and that an additional compound (7.0) blocks EboV and Lassa fever virus infection equally well. These findings suggest that closely related host factors trigger infection by Ebola and Lassa fever viruses, and also that the inhibitors we have identified may be lead compounds for development of new anti-viral drugs.
Intellectual Property Status: Patent(s) Pending
The small molecule inhibitors identified in the lab may be lead compounds for the development of new anti-viral drugs for Ebola and Lassa fever virus.