Viral Fusion Inhibitors

Justification/Summary

Development of anti-DENV therapeutics has been impeded because we know little about the molecular mechanisms of dengue viral processes.  Small molecules can be powerful tools in probing the biochemical pathways associated with dengue viral infection and pathogenesis as well as in identifying potential pharmacological intervention points associated with these viral processes.  The process of dengue viral entry is an especially attractive target for small molecule intervention because it is the first step in the viral life cycle, and inhibition of this step theoretically has the greatest potential to prevent the processes responsible for host pathogenesis before they can occur.  Using a combination of cellular and biochemical screens, Priscilla Yang's group has developed a series of small molecule and peptide-based inhibitors of dengue viral entry.  While these inhibitors are thought to inhibit fusion of the viral and host membranes during the late stages of viral entry and have been found to reduce dengue viral titers by several orders of magnitute in vitro, their detailed mechanism of action remains unknown.

Structural studies are underway to define inhibitor binding sites at high resolution and both cellular and biochemical experiments are being performed to define the inhibitors´┐Ż detailed mechanism(s) of action.  This work includes the selection of resistant mutants which will be sequenced in collaboration with The Broad Institute's Viral Genomics group. Identifying mutations that confer resistance to these inhibitors may provide much needed insight into their respective binding site(s) and mechanism(s) of action.  In addition, the identification of resistance mutations will have important implications for the development of Dengue entry inhibitors as potential therapeutics.    

People

Principal External Collaborator

Priscilla Yang - Dept. of Microbiology, Harvard Medical School, Boston, MA

Funding

Funding for this sequencing project was provided by the National Institute of Allergy and Infectious Diseases.

Whitepaper

Coming soon...

Cohort Description

sm-DVEI - This is an experimental study that looks at how GNF2, a hydrophobic ligand, can decrease viral loads in a cell.  Genomes sequenced as part of this sample set demonstrated the ability to break through the inhibition of GNF2 and lead to 10-fold or greater increases in viral loads.