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

钙依赖性蛋白激酶 1 作为弓形虫和微小弯曲菌的药物靶点

基本信息

批准号：
8288293
负责人：
ETHAN A MERRITT
金额：
$ 99.28万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288293
关键词：
Active Sites Affinity Animal Disease Models Animal Model Animals Binding Binding Sites Bioavailable Biological Assay Cell Culture Techniques Cells Chemicals Complex Consumption Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Data Development Disease Drug Delivery Systems Drug Kinetics Evaluation Food Gatekeeping Homologous Gene Human Infection Invaded Knowledge Lead Libraries Ligands Light Mammalian Cell Mus Organism Parasites Pharmaceutical Preparations Phosphotransferases Positioning Attribute Process Property Protein Kinase Proteins Protozoa Relative (related person)Resistance Side Structure Synthesis Chemistry Toxic effect Toxoplasma Toxoplasma gondii Toxoplasmosis Water Work analog base calcium-dependent protein kinase design follow-up inhibitor/antagonist kinase inhibitor meetings mutant novel therapeutics obligate intracellular parasite pre-clinical scaffold

项目摘要

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.

描述（由申请人提供）：