Nicole Cobb
Graduate Student (Biochemistry)

A.B. Chemistry, Harvard University, 2006.
D321 Fairchild
299 Campus Drive
Stanford CA 94305-5124
Research Summary

The high error rates of viral RNA polymerases allow viral populations to quickly acquire resistance against selective agents, such as antiviral compounds.  A systematic screen of the poliovirus genome has led to the identification of “trans-dominant” mutations: these mutations not only affect the growth of the defective genome, but suppress the growth of co-infecting, non-defective viral genomes (Crowder & Kirkegaard 2005).  Loci containing the “trans-dominant” mutations are excellent drug targets; a small molecule able to modify the dominant drug target should slow overall viral growth.  Even if drug-resistant viral variants arise, the presence of co-infecting, drug-sensitive genomes should render the entire cellular viral population susceptible to suppression.

Mutations that render poliovirus proteinase 2A defective were found to be “trans-dominant.”  Proteinase 2A is responsible for the first proteolytic processing event after viral translation. It intramolecularly cleaves to separate the capsid precursor portion of the viral polyprotein from the non-structural portion. The goal of my project is to determine whether a small molecule inhibitor of poliovirus protease 2A-mediated intramolecular cleavage mimics the “trans-dominant” phenotype observed when the protease is made defective by genetic mutation.  As a proof-of-principle, I will test whether drug-sensitive poliovirus genomes are able to dominantly interfere with the growth of co-infecting drug-resistant genomes and if the emergence of drug resistance is slowed in contrast to the emergence of resistance to a protease inhibitor that does not modify a “dominant drug target.”

Copyright 2006 - 2010. The Laboratory of Karla Kirkegaard, Ph.D. All rights reserved.