A novel calcium-dependent protein kinase inhibitor as a lead compound for treating cryptosporidiosis.

Abstract

Cryptosporidium parasites infect intestinal cells, causing cryptosporidiosis. Despite its high morbidity and association with stunting in the developing world, current therapies for cryptosporidiosis have limited efficacy. Calcium-dependent protein kinases (CDPKs) are essential enzymes in the biology of protozoan parasites. CDPK1 was cloned from the genome of Cryptosporidium parvum, and potent and specific inhibitors have been developed based on structural studies. In this study, we evaluated the anti-Cryptosporidium activity of a novel CDPK1 inhibitor, 1294, and demonstrated that 1294 significantly reduces parasite infection in vitro, with a half maximal effective concentration of 100 nM. Pharmacokinetic studies revealed that 1294 is well absorbed, with a half-life supporting daily administration. Oral therapy with 1294 eliminated Cryptosporidium parasites from 6 of 7 infected severe combined immunodeficiency-beige mice, and the parasites did not recur in these immunosuppressed mice. Mice treated with 1294 had less epithelial damage, corresponding to less apoptosis. Thus, 1294 is an important lead for the development of drugs for treatment of cryptosporidiosis.

• Authors: Alejandro Castellanos-Gonzalez, A Clinton White Jr, Kayode K Ojo, Rama S R Vidadala, Zhongsheng Zhang, Molly C Reid, Anna M W Fox, Katelyn R Keyloun, Kasey Rivas, Ayesha Irani, Sara M Dann, Erkang Fan, Dustin J Maly, Wesley C Van Voorhis
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 208 Issue 8 Pg. 1342-8 (Oct 15 2013) ISSN: 1537-6613 [Electronic] United States
• PMID: 23878324 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiprotozoal Agents
• Protein Kinase Inhibitors
• Protozoan Proteins
• Protein Kinases
• calcium-dependent protein kinase-1, Plasmodium falciparum

Topics

• Animals
• Antiprotozoal Agents (chemistry, pharmacokinetics, pharmacology)
• Apoptosis (drug effects)
• Cell Line
• Cryptosporidiosis (drug therapy, enzymology, parasitology)
• Cryptosporidium parvum (drug effects, enzymology, genetics, isolation & purification)
• Genes, Protozoan
• Humans
• Intestines (parasitology, pathology)
• Mice
• Mice, SCID
• Parasite Load
• Protein Kinase Inhibitors (chemistry, pharmacokinetics, pharmacology)
• Protein Kinases (genetics, metabolism)
• Protozoan Proteins (antagonists & inhibitors, genetics, metabolism)