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 there is an urgent need for improved therapeutics. Parasite surface molecules protect the organisms and enable them to identify, and interact with, cells of both the insect vector and the animal host. Many 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 the 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, proteomics, gene-knockout, cell biology and enzymology approaches to identify, localise and study the functions of glycoprotein and sugar nucleotide biosynthetic enzymes.
(C) Drug Discovery, involving X-ray crystallography and molecular modelling of drug target enzymes, computational chemistry, high-throughput screening and molecular pharmacology and medicinal chemistry (in collaboration with the Drug Discovery Unit).
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 protein phosphorylation in trypanosomes and on biomarker discovery and diagnostic development programmes using advanced proteomics.