Molecular and biochemical parasitology · 2024
Pyridopyrimidinones as a new chemotype of calcium dependent protein kinase 1 (CDPK1) inhibitors for Cryptosporidium.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Waldron-Young Elise, Wijitrmektong Wissarut, Choi Ryan, Whitman Grant R, Hulverson Matthew A, Charania Raheela, Keelaghan Aidan, Li Li, Srinual Songpol, Nikhar Sameer, McNamara Case W, Love Melissa S, Huerta Lauren, Bakowski Malina A, Hu Ming, Van Voorhis Wesley C, Mead Jan R, Cuny Gregory D
Аннотация
The protozoan protein kinase calcium-dependent protein kinase 1 (CDPK1) has emerged as a potential therapeutic target for the treatment of cryptosporidiosis. A focused screen of known kinase inhibitors identified a pyridopyrimidinone as a new chemotype of Cryptosporidium parvum (Cp) CDPK1 inhibitors. Structural comparison of CpCDPK1 to two representative human kinases, RIPK2 and Src, revealed differences in the positioning of the αC-helix that was used in the design of a potent pyridopyrimidinone-based CpCDPK1 inhibitor 7 (a.k.a. UH15-16, IC50 = 10 nM), which blocked the growth of three C. parvum strains (EC50 = 12-40 nM) as well as C. hominis (EC50 = 85 nM) in HCT-8 host cells. Pharmacokinetic and tissue distribution analyses indicated that 7 had low systemic exposure after oral administration, but high gastrointestinal concentration, as well as good Caco-2 cell permeability. Finally, 7 demonstrated partial efficacy in an IL-12 knock-out mouse model of acute cryptosporidiosis.