Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis

Christopher S. Lunde, Erin E. Stebbins, Rajiv S. Jumani, Md Mahmudul Hasan, Peter Miller, John Barlow, Yvonne R. Freund, Pamela Berry, Rianna Stefanakis, Jiri Gut, Philip J. Rosenthal, Melissa S. Love, Case W. McNamara, Eric Easom, Jacob J. Plattner, Robert T. Jacobs and Christopher D. Huston ()
Additional contact information
Christopher S. Lunde: Anacor Pharmaceuticals
Erin E. Stebbins: University of Vermont Robert R. Larner College of Medicine
Rajiv S. Jumani: University of Vermont Robert R. Larner College of Medicine
Md Mahmudul Hasan: University of Vermont Robert R. Larner College of Medicine
Peter Miller: University of Vermont Robert R. Larner College of Medicine
John Barlow: University of Vermont College of Agriculture and Life Sciences
Yvonne R. Freund: Anacor Pharmaceuticals
Pamela Berry: Anacor Pharmaceuticals
Rianna Stefanakis: Anacor Pharmaceuticals
Jiri Gut: University of California San Francisco
Philip J. Rosenthal: University of California San Francisco
Melissa S. Love: Calibr at Scripps Research
Case W. McNamara: Calibr at Scripps Research
Eric Easom: Anacor Pharmaceuticals
Jacob J. Plattner: Anacor Pharmaceuticals
Robert T. Jacobs: Anacor Pharmaceuticals
Christopher D. Huston: University of Vermont Robert R. Larner College of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10687-y

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