1. Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis.
- Author
-
Lunde CS, Stebbins EE, Jumani RS, Hasan MM, Miller P, Barlow J, Freund YR, Berry P, Stefanakis R, Gut J, Rosenthal PJ, Love MS, McNamara CW, Easom E, Plattner JJ, Jacobs RT, and Huston CD
- Subjects
- Amides adverse effects, Amides chemistry, Animals, Antiprotozoal Agents adverse effects, Antiprotozoal Agents chemistry, Boron Compounds adverse effects, Boron Compounds chemistry, Cryptosporidiosis parasitology, Cryptosporidium drug effects, Cryptosporidium growth & development, Drug Evaluation, Preclinical, Female, Humans, Isoxazoles adverse effects, Isoxazoles chemistry, Male, Mice, Rats, Amides administration & dosage, Antiprotozoal Agents administration & dosage, Boron Compounds administration & dosage, Cryptosporidiosis drug therapy, Isoxazoles administration & dosage
- 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.
- Published
- 2019
- Full Text
- View/download PDF