The biosynthesis of glycoproteins in Trypanosoma brucei: basic and translational research.

Sleeping sickness parasites build their surface coats using a precise molecular assembly line, and this project aims to map every step of that process. The parasite *Trypanosoma brucei* causes African sleeping sickness, a fatal disease if untreated. It evades the human immune system by constantly swapping out a dense protein coat on its surface. That coat is built from glycoproteins—proteins with sugar chains attached. This research targets the fundamental biochemistry of how the parasite makes those sugar chains and attaches them to proteins. Without this machinery, the parasite cannot survive or infect. The project will identify the enzymes responsible for each step, from building sugar molecules to stitching them onto proteins, and determine where inside the parasite these reactions occur. If successful, the work will deliver several validated drug targets—specific enzymes that are essential for the parasite but absent or different in humans. These targets will feed directly into a separate drug discovery unit for screening and development of inhibitors. One enzyme, GlcNAc-PI de-N-acetylase, is already a validated target, and the team will design inhibitors against it for structural studies and as starting points for new drugs. This is fundamental science with a clear translational pipeline: understanding the parasite’s basic biology to find chokepoints that drugs can block.