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.
Highlights
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
To meet the need for new anticryptosporidial drug candidates, we adopted a drug repositioning strategy to capitalize on existing benzoxaborole scaffolds and knowledge from advanced programs within Anacor’s Neglected Tropical Disease portfolio, which included antikinetoplastid programs with the Drugs for Neglected Diseases initiative (DNDi) and the Global Alliance for Veterinary Medicine (GALVmed), an antimalarial program with the Medicines for Malaria Venture (MMV), and an internal antibacterial leucyltRNA synthetase (LeuRS) inhibitor program
Further prioritization was done by conducting a preliminary mouse efficacy study with one compound representative of each chemical scaffold that was selected based on availability of chemical stocks, existing potency and mouse PK data, and the potential to leverage other programs within Anacor’s Neglected Tropical Disease portfolio
Summary
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. 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. Plasmodium parasites, which cause malaria, are members of the phylum Apicomplexa, and are genetically related to Cryptosporidium parasites Given this and the recent identification of benzoxaboroles with potent antimalarial activity[28,30,31], we screened a library of benzoxaborole compounds for anticryptosporidial activity. Its initial pharmacokinetic (PK), stability, and safety profiles are highly favorable, and indicate its potential as a new drug for treating cryptosporidiosis in all target populations
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