Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis

Nat Commun. 2019 Jun 27;10(1):2816. doi: 10.1038/s41467-019-10687-y.

Abstract

Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children and causes chronic diarrhea in AIDS patients, but the only approved treatment is ineffective in malnourished children and immunocompromised people. We here use a drug repositioning strategy and identify a promising anticryptosporidial drug candidate. Screening a library of benzoxaboroles comprised of analogs to four antiprotozoal chemical scaffolds under pre-clinical development for neglected tropical diseases for Cryptosporidium growth inhibitors identifies the 6-carboxamide benzoxaborole AN7973. AN7973 blocks intracellular parasite development, appears to be parasiticidal, and potently inhibits the two Cryptosporidium species most relevant to human health, C. parvum and C. hominis. It is efficacious in murine models of both acute and established infection, and in a neonatal dairy calf model of cryptosporidiosis. AN7973 also possesses favorable safety, stability, and PK parameters, and therefore, is an exciting drug candidate for treating cryptosporidiosis.

Publication types

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

MeSH terms

  • Amides / administration & dosage*
  • Amides / adverse effects
  • Amides / chemistry
  • Animals
  • Antiprotozoal Agents / administration & dosage*
  • Antiprotozoal Agents / adverse effects
  • Antiprotozoal Agents / chemistry
  • Boron Compounds / administration & dosage*
  • Boron Compounds / adverse effects
  • Boron Compounds / chemistry
  • Cryptosporidiosis / drug therapy*
  • Cryptosporidiosis / parasitology
  • Cryptosporidium / drug effects
  • Cryptosporidium / growth & development
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Isoxazoles / administration & dosage*
  • Isoxazoles / adverse effects
  • Isoxazoles / chemistry
  • Male
  • Mice
  • Rats

Substances

  • AN7973
  • AN8030
  • Amides
  • Antiprotozoal Agents
  • Boron Compounds
  • Isoxazoles