Pyridopyrimidinones as a new chemotype of calcium dependent protein kinase 1 (CDPK1) inhibitors for Cryptosporidium.

ABSTRACT: 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 syste

SUBMITTER: Waldron-Young E 

PROVIDER: S-EPMC11629397 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature