Position: Professor of Structural Biology
Division: Biological Chemistry and Drug Discovery
Address: College of Life Sciences,
University of Dundee,
Dundee
Telephone: +44 1382 385745, int ext. 85745
Fax: +44 1382 322558
Email: w.n.hunter@dundee.ac.uk
Chemical structure and interactions define biological events and determine how cells or organisms live and die. My research involves elucidation of the relationships that link protein structure to chemical catalysis and biological function. The broad objectives are to determine the mechanisms whereby enzymes catalyze specific, sometimes unusual reactions in metabolite or antibiotic biosynthesis and degradation. The results inform on basic aspects of pathogen biology and a few prized structures represent targets for antimicrobial drug discovery. When such potential targets are identified the focus is to map out the determinants of specificity and inhibition. Understanding why and how small molecules inhibit the target allows us to advance ideas that will ultimately lead to more potent inhibitors designed to assist early stage drug discovery. I have a long-term interest in targeting pathogens such as the Kinetoplastid and Apicomplexan parasites, which present major health and veterinary problems in developing countries.
The urgent need for improved treatments of Gram-negative bacterial infections is also being addressed through a recently established AEROPATH consortium. This European grouping aims to determine new structures of essential proteins from Gram-negative pathogens, in particular Pseudomonas aeruginosa, and exploit the models for ligand identification by compound and virtual screening protocols. These ligands inform on aspects of molecular recognition and serve to guide the design of more potent compounds that represent potential starting points for drug development.
The major technique applied in the laboratory is single crystal X-ray diffraction (Figure 1), a mix of physics, chemistry and biochemistry, and this is aided by additional physical chemistry and biological techniques. Aspects of computational modeling assist our studies and productive collaborations with synthetic chemists provide valued reagents for study.
Specific research areas include:
The biosynthesis of isoprenoid precursors via both the mevalonate and the deoxy-D-xylulose 5-phosphate pathway (DOXP). We have determined structures of GHMP kinase family members from a number of pathogens, and a series of enzyme structures at the core of the DOXP pathway (1,2). Inhibitors against a number of these enzymes are now being sought.
Pterin/folate metabolism. Pteridine reductase (PTR1), an NADPH-dependent short-chain reductase, participates in the salvage of pterins by parasitic trypanosomatid protozoans, which are essential for parasite growth. PTR1 displays broad-spectrum activity with pterins and folates, provides a metabolic by-pass for inhibition of the trypanosomatid dihydrofolate reductase and compromises the use of antifolates for treatment of trypanosomiasis. Our characterization of PTR1 and numerous inhibitor complexes (Figure 2) is providing new scaffolds to aid the search for highly potent PTR1 inhibitors (3).
Our work promotes understanding of how existing drugs work, and the success with nicotinamidase has revealed the mode of activation of a front line antituberculosis drug (4, Figure 3). More recently, research to dissect the pathways that direct vitamin K (an essential metabolite) biosynthesis together with a longer-term projects to understand how glycosylphosphatidylinositol anchored glycoproteins and related glycolipids are assembled has been initiated (5).
Our research is funded by BBSRC, The Wellcome Trust and the European Commission.
