My research interests lie at the interface of chemistry and biology, utilising synthetic organic chemistry to investigate biological systems. I am involved in the design, synthesis and use of substrate derivatives as tools to study enzymes of biological and medical importance, with a particular emphasis on carbohydrate processing enzymes. These studies range from detailed investigations into the catalytic mechanisms of enzymes, to the use of this information in the design and synthesis of compounds as potential drug candidates. Some of the current research projects in my group include:

Inhibitors of HIV Integrase

HIV integrase is an enzyme expressed by the HIV virus. Integrase catalyses the incorporation of viral DNA into the genome of the host and as such, is essential for the survival and proliferation of the virus. Integrase is seen as a promising target for the chemotherapeutic treatment of HIV, yet little is known about the precise chemical mechanism through which the enzyme catalyses the integration of viral DNA.

My group is using chemically modified oligonucleotides in combination with protein X-ray crystallography (collaboration with Prof. Gideon Davies, University of York) to characterise crucial DNA-protein binding interactions, as well as the conformation changes the enzyme undergoes upon binding of viral and host DNA. This work will give us a detailed understanding of the catalytic mechanism of HIV integrase.

Information gained on the catalytic mechanism will then used to design and synthesise ‘mechanism-based’ inhibitors specific for HIV integrase.

Mechanism-based Inhibitors of Influenza Neuraminidases

Neuraminidases are enzymes that catalyse the removal of sialic acid residues from various glycoconjugates. The activity of these enzymes is known to be essential for the virulence and survival of several pathogens including the influenza virus. Consequently, influenza neuraminidase has emerged as a target enzyme for the development of anti-viral therapeutics. Indeed two neuraminidase inhibitors are currently marketed as drugs for influenza, namely Relenza® and Tamiflu®. However, it has recently emerged that strains of avian influenza, or 'Bird Flu', have already shown resistance to Tamiflu®. As many today consider that a new and devastating influenza pandemic is inevitable, there is an urgent need to develop new classes of antiviral compounds less susceptible to drug-induced resistance. Work in the laboratory of Prof. Steve Withers (UBC, Vancouver) has shown that fluorinated sialic acid analogues act as ‘mechanism-based’ inactivators to inhibit influenza neuraminidases. These compounds inhibit influenza neuraminidases by specifically targeting crucial residues of the enzyme essential for catalysis. As the neuraminidase is unable to tolerate mutations to these essential residues, drug-induced resistance is less likely to evolve in response to compounds.