Schistosomiasis, a parasitic disease caused by blood flukes of the genus Schistosoma, is a global health problem with over 240 million people infected. Treatment relies on just one drug, and new therapies are needed. Adult schistosomes live in the cardiovascular system, and host blood proteins are a primary source of nutrients. In the schistosome gut, a network of proteases performs the digestion of host proteins and represents a potential intervention target. Schistosoma mansoni cathepsin D (SmCD) is a pepsin-family aspartic protease that initiates host hemoglobin digestion in schistosomes.
Recombinant SmCD was produced in the Leishmania tarantolae protozoan expression system. Screening of a library of more than 30 macrocyclic statin-based peptidomimetics against SmCD selected potent inhibitors with low nanomolar activity. These inhibitors displayed anti-schistosomal properties and thus represent a new lead scaffold for developing potential drugs for schistosomiasis treatment. Furthermore, we solved the crystal structure of the SmCD zymogen, and currently we are working on the structural analysis of SmCD complexes with macrocyclic inhibitors.