A Novel Piperazine-Based Drug Lead for Cryptosporidiosis from the Medicines for Malaria Venture Open Access Malaria Box [PublishAheadOfPrint]

Cryptosporidiosis causes life-threatening diarrhea in children under age five, and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to a need for new drugs, better knowledge of drug properties that drive in vivo efficacy is needed to facilitate drug development. We report identification of a piperazine-based lead compound for Cryptosporidium drug development, MMV665917, and a new pharmacodynamic method used for its characterization. MMV665917 was identified from the Medicines for Malaria Venture Malaria Box, followed by dose response studies, in vitro toxicity studies, and structure activity relationship studies using commercial analogues. Potency against C. parvum Iowa and field isolates, and C. hominis was comparable. Furthermore, unlike nitazoxanide, clofazimine, and paromomycin, MMV665917 appeared to be curative in a chronic NOD SCID gamma mouse model of cryptosporidiosis. MMV665917 was also efficacious in an acute interferon- knockout mouse model. To determine if efficacy in this chronic mouse model might relate to whether compounds are cidal or static for C. parvum, we developed a novel in vitro parasite persistence assay. This assay suggested that MMV665917 was cidal, unlike nitazoxanide, clofazimine, and paromomycin. It also enabled determination of the compound concentration required to maximize the rate of parasite elimination. This time-kill assay can be used to prioritize early-stage Cryptosporidium drug leads, and may aide in planning in vivo efficacy experiments. Collectively, these results identify MMV665917 as a promising lead, and establish a new method for characterizing potential anticryptosporidial agents.

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