SEMINAR: Bayliss Seminar Series: Ethan Merritt

The MSGPP collaboration has used structural genomics, targeted genetics, and synthetic chemistry to identify, validate, and exploit potential drug targets in parasitic protozoa. One notable success from this approach has targeted Calcium-Dependent Protein Kinases (CDPKs), a class of proteins found in plants and in apicomplexa but not in the multicellular animals that are the hosts and victims of these parasites. CDPKs regulate various essential life‐cycle processes in Toxoplasma, Cryptosporidium, Plasmodium and related species. Some CDPKs, including CDPK1 from T. gondii and C. parvum, and CDPK4 from P. faciparum, fortuitously exhibit atypical features in the kinase active site that allow the development of inhibitors highly selective for the parasite kinase over all human kinases. Inhibition of TgCDPK1 or CpCDPK1 interferes with invasion of host cells, blocking parasite proliferation. Inhibition of PfCDPK4 blocks transmission of malaria by mosquitoes. Paired crystal structures of inhibitors in complex with CDPK1 and the representative human kinase c‐SRC allowed us to dissect key features of the respective binding sites. This provided a model for the structure/activity relationships (SAR) that underly the specificity observed for an initial series of compounds based on a pyrazolopyrimidine scaffold. We applied this SAR model to transform two additional chemical scaffolds, initially lacking potency and selectivity, into low nanomolar inhibitors of CDPK1 with no little to no activity against human kinases. Compounds from two scaffold series with low toxicity and good PK/ADME properties have progressed into animal trials as anticoccidial agents. Other compounds show efficacy in treating mouse models of toxoplasmosis.