Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondii

Florentine U. Rutaganira, Jennifer Barks, Mary Savari Dhason, Qiuling Wang, Michael S. Lopez, Shaojun Long, Joshua B. Radke, Nathaniel G. Jones, Amarendar R. Maddirala, James W. Janetka, Majida El Bakkouri, Raymond Hui, Kevan M. Shokat, L. David Sibley

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)9976-9989
Number of pages14
JournalJournal of Medicinal Chemistry
Volume60
Issue number24
DOIs
StatePublished - Dec 28 2017

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    Rutaganira, F. U., Barks, J., Dhason, M. S., Wang, Q., Lopez, M. S., Long, S., Radke, J. B., Jones, N. G., Maddirala, A. R., Janetka, J. W., El Bakkouri, M., Hui, R., Shokat, K. M., & Sibley, L. D. (2017). Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondii. Journal of Medicinal Chemistry, 60(24), 9976-9989. https://doi.org/10.1021/acs.jmedchem.7b01192