Combating Schistosoma mansoni by targeting proteasome and a gut-maintaining gene and the discovery of novel serine protease inhibitors in cyanobacteria

Project 1: Schistosomiasis is a neglected tropical disease with a single drug available: Praziquantel. Using substrate profiling by mass spectrometry on S. mansoni proteasome, we obtained the substrate specificity profile for the β1, β2 and β5 subunits of the proteasome. Novel fluorogenic substrates were designed. The new β5 substrate (FNKL-AMC) proved to be much more potent than the commercial substrate (LLVY-AMC). These substrates demonstrated similar activity in three Schistosoma species, proving that they can detect proteasome activity in more than just S. mansoni. Project 2: Finding novel drug targets within the parasite is needed. Dr. James Collins and his team performed a comprehensive single-cell RNAseq on adult Schistosoma. They categorized 43,642 cells and assigned them into 68 distinctive populations. A homologue of hepatocyte nuclear factor 4 (hnf4) was discovered in a lineage of gut cells. The cathepsin activity in worms that received RNAi of hnf4 was measured. It was revealed that cathepsin B activity was decreased 8.2-fold relative to the control group. I showed that hnf4 is essential for the cathepsin-mediated hemoglobin digestion of S. mansoni. Project 3: Marine natural products possess diverse biological activities. IC50 values of Tutuilamide A-C and two additional analogues were calculated for pancreatic elastase, fungal proteinase K, trypsin, and chymotrypsin. Tutuilamide A and B demonstrated potent IC50 values against pancreatic elastase (1.18 nM and 2.05 nM, respectively) and proteinase K (103.7 nM and 87.6 nM, respectively). These compounds proved to be 2 to 4-fold more potent compared to previously studied elastase inhibitor lyngbyastatin 7