Optimizing small molecule inhibitors of calcium-dependent protein kinase 1 to prevent infection by toxoplasma gondii

Sebastian Lourido, Chao Zhang, Michael S. Lopez, Keliang Tang, Jennifer Barks, Qiuling Wang, Scott A. Wildman, Kevan M. Shokat, L. David Sibley

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Toxoplasma gondii is sensitive to bulky pyrazolo [3,4-d] pyrimidine (PP) inhibitors due to the presence of a Gly gatekeeper in the essential calcium dependent protein kinase 1 (CDPK1). Here we synthesized a number of new derivatives of 3-methyl-benzyl-PP (3-MB-PP, or 1). The potency of PP analogues in inhibiting CDPK1 enzyme activity in vitro (low nM IC50 values) and blocking parasite growth in host cell monolayers in vivo (low μM EC 50 values) were highly correlated and occurred in a CDPK1-specific manner. Chemical modification of the PP scaffold to increase half-life in the presence of microsomes in vitro led to identification of compounds with enhanced stability while retaining activity. Several of these more potent compounds were able to prevent lethal infection with T. gondii in the mouse model. Collectively, the strategies outlined here provide a route for development of more effective compounds for treatment of toxoplasmosis and perhaps related parasitic diseases.

Original languageEnglish
Pages (from-to)3068-3077
Number of pages10
JournalJournal of Medicinal Chemistry
Volume56
Issue number7
DOIs
StatePublished - Apr 11 2013

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