The parasite Trypanosoma cruzi is the etiological agent for Chagas disease, a debilitating and often fatal condition prevalent in South and Central America. With more than 20 million people infected the parasite poses a major health threat. The parasite uses sialic acid containing mucins to adhere to cells of the infected host, a prerequisite for cell invasion and parasite replication. However, T. cruzi is unable to synthesize the carbohydrate sialic acid de novo; instead it uses a trans-sialidase to scavenge this sugar from glycoconjugates of the infected host. Both the absence of trans-sialidase in mammals and its role in T. cruzi infectivity identify this enzyme as a potential target for therapeutic intervention. This project aims to determine the molecular detail of trans-sialidase substrate recognition and mechanism of action, which will provide new insights into the design and development of potential antibiotics. Our hypothesis is that a reductionism approach, employing model substrate analogues, is out of context and that we will only really learn how the enzyme works by analysing its interactions with the T. cruzi mucin glycopeptides that serve as substrates for the enzyme in vivo. It is not possible to obtain such materials in quantity, or in homogeneous form, from natural isolates.
The purpose of this project is to use a combination of state-of-the-art chemical and enzymatic synthesis to access homogeneous mucin glycopeptide fragments with which to probe specific issues about substrate recognition and turnover by trans-sialidase. This study serves to emphasise the key role for synthetic organic chemistry in post-genomic science, enabling structural biology and providing tools to delineate biological function. The project builds on the applicant’s expertise in synthetic and bioorganic chemistry, obtained during PhD studies with van Boom in Leiden (Netherlands), and applies it to an enzymology/chemical biology-led programme with Field in Norwich (UK).
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