title: 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.affiliation: Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Castellanos-Gonzalez
authors.forename: A Clinton
authors.initials: AC
authors.lastname: White
authors.forename: Kayode K
authors.initials: KK
authors.lastname: Ojo
authors.forename: Rama S R
authors.initials: RS
authors.lastname: Vidadala
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Molly C
authors.initials: MC
authors.lastname: Reid
authors.forename: Anna M W
authors.initials: AM
authors.lastname: Fox
authors.forename: Katelyn R
authors.initials: KR
authors.lastname: Keyloun
authors.forename: Kasey
authors.initials: K
authors.lastname: Rivas
authors.forename: Ayesha
authors.initials: A
authors.lastname: Irani
authors.forename: Sara M
authors.initials: SM
authors.lastname: Dann
authors.forename: Erkang
authors.initials: E
authors.lastname: Fan
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Maly
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D003457:Cryptosporidiosis / Q000188:drug therapy* / Q000201:enzymology / Q000469:parasitology; D016785:Cryptosporidium parvum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification; D017125:Genes, Protozoan; D006801:Humans; D007422:Intestines / Q000469:parasitology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D059208:Parasite Load; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D047428:Protein Kinase Inhibitors; D015800:Protozoan Proteins; D011494:Protein Kinases; C531238:calcium-dependent protein kinase-1, Plasmodium falciparum
keywords: Calcium-dependant Protein kinase; CpCDPK-1; Cryptosporidium parvum; antiparasitic; bumped kinase inhibitor; cryptosporidiosis