Henry Wellcome Building of Genomic Medicine
Viruses are relatively simple biological systems and as such a structural analysis of viruses allows fundamental biological questions to be addressed. Examples include protein recognition events involved in macromolecular capsid assembly, genome replication and mRNA synthesis as well as evasion of the host cells immune system. I work on a number of viruses that target some of these key biological events ranging from viral capsids to individual viral proteins, using a variety of biophysical techniques, primarily crystallography
dsRNA viruses are attractive systems due to the constraints imposed on their biology. Because of the poisonous nature of their dsRNA genomes, the viral core containing the genome remains intact within the infected cell. The core is an efficient transcription machine which has all the required enzyme activities necessary to produce capped mRNA. Unravelling the action of these viral enzymes has remained a key focus, particularly the polymerase structures from these dsRNA viruses.
Another area of research involves a study of immunomodulators of vaccinia virus. Over half the genome of vaccinia virus is composed of non-essential genes for virus replication in cell culture. They code for proteins that effect virus virulance, host cell susceptibility or the host response to infection. We have demonstrated the potential of high-throughput structural methods to contribute in a timely way to functional analysis. Four novel structures have already been determined. Currently we have focused our energies on replicative enzymes of flaviviruses but are now targeting the more challenging polymerases of certain -ve ssRNA viruses.
Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19
Peng Y. et al, (2020), Nature Immunology, 21, 1336 - 1345
3D Correlative Cryo-Structured Illumination Fluorescence and Soft X-ray Microscopy Elucidates Reovirus Intracellular Release Pathway.
Kounatidis I. et al, (2020), Cell, 182, 515 - 530.e17
Enisamium is a small molecule inhibitor of the influenza A virus and SARS-CoV-2 RNA polymerases.
Walker AP. et al, (2020), bioRxiv : the preprint server for biology
High-resolution crystal structure of arthropod Eiger TNF suggests a mode of receptor engagement and altered surface charge within endosomes
Bertinelli M. et al, (2019), Communications Biology, 2
Design, Synthesis, and Biological Evaluation of Novel Indoles Targeting the Influenza PB2 Cap Binding Region
McGowan DC. et al, (2019), Journal of Medicinal Chemistry, 62, 9680 - 9690