Our Research
Insect-transmitted protozoan parasites cause widespread and debilitating diseases in man and domestic livestock throughout the tropics. Examples of diseases caused by trypanosomatid parasites include African sleeping sickness (caused by Trypanosoma brucei and transmitted by tsetse flies), Chagas disease (caused by Trypanosoma cruzi) and kala-azar, espundia and oriental sore (caused by the Leishmania). There are no vaccines against these diseases and most of the available drug treatments are toxic and/or ineffective.
Parasite surface molecules protect the organisms and enable them to identify, and interact with, cells of both the insect vector and the animal host. Most trypanosomatid parasite surface molecules are either glycosylphosphatidylinositol (GPI) anchored glycoproteins or GPI-related glycolipids.
The parasite GPI biosynthetic pathway, and the pathways that assemble the sugar nucleotides that fuel it and protein O- and N-glycosylation pathways, are validated targets for the development of new chemotherapeutic agents.
Our research is multi-disciplinary and involves defining:
- The "structural repertoire" of the parasite glycoproteins.
- The "biosynthetic repertoire" of necessary glycosyltransferases and processing enzymes needed to create the structural repertoire.
- The "metabolic repertoire" of sugar nucleotides, and their biosynthetic and transporter proteins, needed to fuel the biosynthetic repertoire.
These goals involve:
(A) The isolation and analysis of parasite surface molecules using advanced mass spectrometric methods.
(B) Bioinformatics (in collaboration with Geoff Barton and David Martin), proteomics, gene-knockout and cell biology approaches to identify, localise and study the functions of glycoprotein and sugar nucleotide biosynthetic enzymes.
(C) Synthetic organic chemistry (including collaborations with Andrei Nikolaev and Ian Gilbert) and enzymology to define the properties and substrate specificities of enzymes involved in protein glycosylation, GPI anchor biosynthesis and sugar nucleotide assembly.
(D) Drug Discovery, involving X-ray crystallography and molecular modelling of drug target enzymes (in collaboration with Bill Hunter and Daan van Aalten), computational chemistry (in collaboration with Ruth Brenk), high-throughput screening and molecular pharmacology (in collaboration with Julie Frearson) and medicinal chemistry (in collaboration with Ian Gilbert and Paul Wyatt).
Our ultimate aim is to discover new anti-parasite therapeutic agents for clinical trials through our unique Drug Discovery Unit
In addition to parasite glycobiology, we also work on biomarker discovery programmes using advanced proteomics with our colleagues in the medical school. These include Dr John Dillon, Professor Bob Steele, Professor Roland Wolf, Professor Andrew Morris and Professor Helen Colhoun.