Pyridopyrimidinones as a new chemotype of calcium dependent protein kinase 1 (CDPK1) inhibitors for Cryptosporidium.
Elise Waldron-YoungWissarut WijitrmektongRyan ChoiGrant R WhitmanMatthew A HulversonRaheela CharaniaAidan KeelaghanLi LiSongpol SrinualSameer NikharCase W McNamaraMelissa S LoveLauren HuertaMalina A BakowskiMing HuWesley C Van VoorhisJan R MeadGregory D CunyPublished in: Molecular and biochemical parasitology (2024)
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, IC 50 = 10 nM), which blocked the growth of three C. parvum strains (EC 50 = 12-40 nM) as well as C. hominis (EC 50 = 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.
Keyphrases
- protein kinase
- photodynamic therapy
- endothelial cells
- mouse model
- cell cycle arrest
- single cell
- induced apoptosis
- liver failure
- escherichia coli
- high throughput
- drug induced
- cell death
- respiratory failure
- tyrosine kinase
- light emitting
- cross sectional
- induced pluripotent stem cells
- pluripotent stem cells
- signaling pathway
- combination therapy
- oxidative stress
- intensive care unit
- anti inflammatory
- acute respiratory distress syndrome
- clinical evaluation