Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondii
| Autor: | Amarendar Reddy Maddirala, Jennifer Barks, Kevan M. Shokat, Nathaniel G. Jones, James W. Janetka, Majida El Bakkouri, Shaojun Long, Michael S. Lopez, Raymond Hui, L. David Sibley, Mary Savari Dhason, Qiuling Wang, Joshua B. Radke, Florentine U. Rutaganira |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine 030106 microbiology Antiprotozoal Agents Protozoan Proteins Article Pyrazolopyrimidine Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Drug Discovery Animals Humans Structure–activity relationship Secretion Protein Kinase Inhibitors chemistry.chemical_classification biology Chemistry Toxoplasma gondii biology.organism_classification In vitro Pyrimidines 030104 developmental biology Enzyme Biochemistry Toxoplasmosis Cerebral Glycine Pyrazoles Molecular Medicine Female Protein Kinases Toxoplasma Intracellular |
| Zdroj: | Journal of Medicinal Chemistry. 60:9976-9989 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are critical to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compound 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, and decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small molecule inhibitors of CDPK1 for treatment of CNS toxoplasmosis. |
| Databáze: | OpenAIRE |
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