The goal of this Center for Excellence in Translational Research is to develop small molecule inhibitors of enveloped virus entry and test their efficacy in animal models of disease. The underlying hypothesis is that enveloped viral entry is replete with therapeutic targets to which small molecule inhibitors can be developed, blocking receptor engagement, membrane fusion, and cellular trafficking. Most classes of licensed antiviral drugs block intracellular steps of the replication cycle, often through interfering with virally encoded enzymes required for replication. A handful of antiviral agents block enveloped virus entry: maraviroc, a small molecule that blocks engagement of the CCR5 co-receptor by gp120 of human immunodeficiency virus-1;enfuvirtide, a synthetic peptide that binds gp41 of HIV1 and interferes with fusion;and amantadine/rimantidine, which blocks the M2 ion channel of certain strains of influenza A virus to prevent release of the viral ribonucleoprotein segments into the cell. That paucity of synthetic entry inhibitors starkly contrasts with the natural protection mechanism of neutralizing antibodies that frequently block viral entry. This CETR will advance two general approaches to small molecule inhibition of viral entry: direct targeting of viral envelope proteins;and specific targeting of cellular factors requisite for infectious virus entry. Targeting envelope proteins has the advantage that the small molecules do not need to enter cells, thus eliminating uptake and potential export concerns, and such inhibitors may be less likely to have unwanted interactions with cellular proteins. Targeting cellular proteins offers the attractive though unproven possibility to inhibit the entry of multiple viruses with a single small molecule. A team of 6 investigators working on interdependent projects will discover and advance small molecule inhibitors of both categories.
Both flaviviruses and filoviruses are serious pathogens with critical unmet clinical needs. Flaviviruses, including dengue virus, West Nile virus, and yellow fever virus, are widespread arthropod-transmitted human pathogens. Approximately 100 million people are infected with dengue alone each year. Although the filoviruses such as Ebola virus and Marburg virus are not as widespread as the flaviviruses, case fatality rates can approach 90%. This program seeks to identify new candidate therapeutic compounds to address these important human pathogens.
|Carocci, Margot; Hinshaw, Stephen M; Rodgers, Mary A et al. (2015) The bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus replication. Antimicrob Agents Chemother 59:85-95|
|Chao, Luke H; Klein, Daryl E; Schmidt, Aaron G et al. (2014) Sequential conformational rearrangements in flavivirus membrane fusion. Elife 3:e04389|
|Jae, Lucas T; Raaben, Matthijs; Herbert, Andrew S et al. (2014) Virus entry. Lassa virus entry requires a trigger-induced receptor switch. Science 344:1506-10|