Invariant surface glycoproteins of trypanosomes as targets for structure-guided drug and vaccine design

Sebastian Zoll, Jakub Began, Hagen Suelzen, Jitka Votrubova

Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 542/2, 166 10 Prague

Sleeping sickness caused by several Trypanosoma species is a neglected and mostly fatal disease that causes thousands of human deaths each year and has tremendous economic impact due to considerable losses in livestock. Yet no vaccine exists due to elaborate immune evasion mechanisms and the few available drugs exhibit high toxicity, narrow specificity and their efficacy is undermined by the emergence of drug

resistances. The absence of a vaccine has put synthetic compounds into the first line of defence against sleeping sickness, but the currently available drugs were all invented before the advent of target-based drug design and although the protein networks that contribute to their efficacy have now been identified, the mechanisms by which they take action and are transported across the plasma still remain unknown. Not at last this is due to the surprising lack of structural information on receptor/transporter-drug complexes, making it impossible to improve drug

tolerability/efficacy or modify drugs in response to resistance formation. Invariant surface glycoproteins (ISGs), a structurally uncharacterized group of type I transmembrane proteins, exclusively expressed in blood stream forms of trypanosomes, are appealing targets for both vaccine as well as drug design. We are currently investigating the roles of two members of this group, ISG75 and ISG65 using Cryo-EM as well as X-ray crystallography. The structures of these proteins in complex with their natural ligands will allow us to design compounds that disrupt these interaction to work as a new class of anti-trypanosomal therapeutics.