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Professor Ian Goodfellow

Abstract:

Characterisation and inhibition of the novel mechanism of norovirus VPg-dependent translation initiation: A new therapeutic approach for ‘Winter Vomiting Disease’     

As obligate intracellular pathogens, viruses rely exclusively on the host cell for the components of the protein synthesis machinery and have evolved a multitude of mechanisms to enable the translation of viral mRNA into protein in the presence of high concentrations of competing cellular mRNA.    

Noroviruses, members of the Caliciviridae family of small positive strand RNA viruses, are the major cause of acute viral gastroenteritis in man and result in up to 6 million cases of ‘Winter Vomiting Disease’ in the UK each year. Due to their economic impact, the development of therapeutic approaches and vaccines against noroviruses is of high priority.    We have previous reported the identification of a novel mechanism of viral protein synthesis used by members of the calicivirus family, which relies on the interaction of translation initiation factors with a virus encoded protein covalently linked to the 5’ end of the viral RNA genome. This mechanism is unique to noroviruses and provides a good target for therapeutic intervention.    This project aims to build on our previous and ongoing studies on the novel mechanism of norovirus translation initiation and to define the cellular translation initiation factors require for human norovirus translation initiation. It uses recently developed experimental tools state of the art approaches to define the cellular initiation factors required for norovirus translation.   

The specific aims of the project include: 

  1. Characterization of the mechanism of human norovirus translation initiation 
  2. Development of assays suitable for high-throughput identification of inhibitors of norovirus translation initiation    Experimental approaches will include state of the art quantitative proteomics, in vitro biochemical analysis of protein-protein interactions, reverse genetics, protein expression and purification, cell culture etc.

References:

  1. Goodfellow, I. (2011). The genome-linked protein VPg of vertebrate viruses — a multifaceted protein. Current Opinion in Virology, 1(5), 355–362. doi:10.1016/j.coviro.2011.09.003    
  2. Chaudhry, Y., Nayak, A., Bordeleau, M.-E., Tanaka, J., Pelletier, J., Belsham, G. J., et al. (2006). Caliciviruses differ in their functional requirements for eIF4F components. The Journal of Biological Chemistry, 281(35), 25315–25325. doi:10.1074/jbc.M602230200      
  3. Goodfellow, I., Chaudhry, Y., Gioldasi, I., Gerondopoulos, A., Natoni, A., Labrie, L., et al. (2005). Calicivirus translation initiation requires an interaction between VPg and eIF 4 E. EMBO Reports, 6(10), 968–972. doi:10.1038/sj.embor.7400510