The hepatitis C virus (HCV) is a serious health concern, causing significant morbidity and mortality and affecting 50 million people globally. The limited number of effective drugs available is concerning, especially when you consider the ability of viruses to rapidly evolve and develop drug resistance. This project focuses on the HCV polymerase, a target for sofosbuvir (SOF), a drug that transformed the treatment of HCV in 2015. SOF works by mimicking a natural nucleotide, becoming incorporated into the synthesised RNA strand and consequently inhibiting RNA synthesis. Therefore, to understand HCV resistance to SOF at a molecular level, it is essential to study drug interactions within biologically relevant polymerase structures with RNA bound. While we have obtained a polymerase-RNA structure for HCV genotype 2, there are currently no such structures available for the clinically important genotypes 1 and 3, which account for 67% of all infections.
The aims of this project are:
- to obtain polymerase-RNA-SOF crystal structures for HCV genotypes 1 and 3; and
- to obtain room-temperature polymerase-RNA-SOF crystal structures for HCV genotype 2.
These structures will be instrumental in studying polymerase-SOF interactions and how polymerase mutations cause resistance.
This project will draw on the expertise and cutting-edge facilities of the MAX IV Laboratory, the experience of the University of Copenhagen in crystallising HCV polymerases, and the clinical perspective on antiviral resistance from Hvidovre Hospital.
Figure 1. Crystal structure of HCV genotype 2 polymerase with RNA (yellow), Mn2+ (red) and incoming nucleotide (blue) bound.
For further information about this HALRIC pilot project, please contact:
Line Abildgaard Ryberg
University of Copenhagen
line.ryberg@sund.ku.dk
