Professor Mark Harris
My research seeks to understand the molecular mechanisms underpinning the replication of two positive strand RNA viruses that are important human pathogens, hepatitis C virus (HCV) and Chikungunya virus (CHIKV). In particular we wish to understand how these viruses replicate their RNA genomes and interact with host cell proteins. We hope that this information will lead to the development of novel, much needed, therapeutics. We are also working with colleagues in the School of Chemistry to develop novel antivirals to block the replication of SARS-CoV-2, the causative agent of the current pandemic, and Ebola virus which has caused significant outbreaks in Western Africa over the past 5 years.
Current major projects
- Structure and composition of positive strand RNA virus replication complexes
- Functional studies on viral non-structural proteins
- Structure-based drug design to develop new antivirals
Detailed Research programme
Structure and composition of positive strand RNA virus replication complexes
Our primary aim is to understand mechanisms of virus replication and pathogenesis with a view to developing new therapeutic options. For hepatitis C virus (HCV) and Chikungunya (CHIKV) we are applying a similar range of technical approaches – for example proteomic analysis to determine the interactomes of key viral non-structural proteins (HCV NS5A and CHIKV nsP3).
We are using imaging techniques to probe the multiprotein complexes that replicate the viral genome. These include genetically tagging these viruses to enable either high resolution cryo-EM or fluorescent imaging, in collaboration with Juan Fontana and Michelle Peckham (Leeds). In particular we are utilising a confocal microscope located within the BSL3 containment facility – a unique resource within the UK for the study of HCV and CHIKV.
We intend to broaden these studies to encompass SAR-CoV-2 – our facilities enable us to propagate and study this virus.
Functional studies on viral non-structural proteins
A major focus is the role of phosphorylation in regulating the interactome and the different functions of these proteins. We are following our mass spectrometric analysis of sites of phosphorylation in NS5A with a functional analysis of the role of this post-translational modification in virus replication. We are also investigating the role of viral non-structural proteins in the process of virus assembly, an area that is currently poorly understood.
Structure-based drug design to develop new antivirals
In collaboration with Colin Fishwick and Martin McPhillie (Leeds) we are applying structure-based drug design methodology to viral proteins. In particular we have used this approach to develop small molecule inhibitors of EBOV replication which we hope may form the basis for a novel future therapeutic approach. This project utilises a mini-genome system which does not require growth of this highly pathogenic virus, but recapitulates key events in the virus lifecycle. We wish to apply this approach to SARS-CoV-2, utilising the BSL3 containment facility to propagate this virus.
An alternative approach to development of antivirals comes from a collaboration with colleagues in Brazil (Carol Jardim, Uberlandia and Paula Rahal, Sao Paolo) to exploit the unique flora of that country as templates to develop potential pharmacologically active compounds.