Calcium Dependent Protein Kinase 1 as a drug target for T. gondii and C. parvum

University Of Washington, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): New therapeutics are needed for infections caused by Cryptosporidium parvum and Toxoplasma gondii. Calcium dependent protein kinase 1 (CDPK1) of T. gondii is thought to be critical for the invasion process of T. gondii and thus is a drug target for toxoplasmosis. By inference, the homologous CDPK of C. parvum is likely to be critical for infection by cryptosporidium. We have solved the crystal structures of TgCDPK1 and CpCDPK1 and have shown the active sites are susceptible to "bumped" kinase inhibitors (BKI) that do not inhibit mammalian kinases. This differential sensitivity is due to the absence of a bulky gatekeeper side chain in the ATP binding site of both TgCDPK1 and CpCDPK1 that is present in mammalian protein kinases. Thus, these BKI offer tremendous selectivity for inhibition of TgCDPK1 &CpCDPK1 vs. human kinases. Furthermore, BKI compounds have shown minimal toxicity in mice when administered in the course of other work. Our preliminary results show that multiple BKI compounds based on a known scaffold can inhibit TgCDPK1 &CpCDPK1 and also inhibit T. gondii and C. parvum cell invasion at low-mid nanomolar concentrations. Expression of a mutant TgCDPK1 with a Met gatekeeper in T. gondii cells leads to resistance to the BKI effect, demonstrating the BKI inhibits cell entry via CDPK1. We will develop compounds that are orally bioavailable, sufficiently potent, lack toxicity, and cure animal models of T. gondii and/or C. parvum. By the end of this project we expect to identify and characterize 2 to 4 leads for evaluation as potential drugs for cryptosporidiosis and toxoplasmosis. This project will initiate development of new drugs to treat diseases caused by two parasitic protozoa, Cryptosporidium and Toxoplasma that are commonly transmitted by consumption of impure food or water. We have identified a class of chemical compounds that specifically inhibit a particular protein used by these parasites to invade human cells. We will design and characterize compounds of this class that are nontoxic to humans but effective in treating infection. Relevance: This project will initiate development of new drugs to treat diseases caused by two parasitic protozoa, Cryptosporidium and Toxoplasma, that are commonly transmitted by consumption of impure food or water. We have identified a class of chemical compounds that specifically inhibit a particular protein used by these parasites to invade human cells. We will design and characterize compounds of this class that are nontoxic to humans but effective in treating infection.