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

J Infect Dis. 2013 Oct 15;208(8):1342-8. doi: 10.1093/infdis/jit327. Epub 2013 Jul 21.

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.

Keywords: Calcium-dependant Protein kinase; CpCDPK-1; Cryptosporidium parvum; antiparasitic; bumped kinase inhibitor; cryptosporidiosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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