Bicyclic azetidines kill the diarrheal pathogen Cryptosporidium in mice by inhibiting parasite phenylalanyl-tRNA synthetase

Sumiti Vinayak, Rajiv S. Jumani, Peter Miller, Muhammad M. Hasan, Briana I. Mcleod, Jayesh Tandel, Erin E. Stebbins, Jose E. Teixeira, Julien Borrel, Arthur Gonse, Mingliang Zhang, Xianshui Yu, Amy Wernimont, Chris Walpole, Sean Eckley, Melissa S. Love, Case W. Mcnamara, Manmohan Sharma, Amit Sharma, Christina A. SchererNobutaka Kato, Stuart L. Schreiber, Bruno Melillo, Boris Striepen, Christopher D. Huston, Eamon Comer

Research output: Contribution to journalArticlepeer-review

Abstract

Cryptosporidium is a protozoan parasite and a leading cause of diarrheal disease and mortality in young children. Currently, there are no fully effective treatments available to cure infection with this diarrheal pathogen. In this study, we report a broad drug repositioning effort that led to the identification of bicyclic azetidines as a new anticryptosporidial series. Members of this series blocked growth in in vitro culture of three Cryptosporidium parvum isolates with EC50’s in 1% serum of <0.4 to 96 nM, had comparable potencies against Cryptosporidium hominis and C. parvum, and was effective in three of four highly susceptible immunosuppressed mice with once-daily dosing administered for 4 days beginning 2 weeks after infection. Comprehensive genetic, biochemical, and chemical studies demonstrated inhibition of C. parvum phenylalanyl-tRNA synthetase (CpPheRS) as the mode of action of this new lead series. Introduction of mutations directly into the C. parvum pheRS gene by CRISPR-Cas9 genome editing resulted in parasites showing high degrees of compound resistance. In vitro, bicyclic azetidines potently inhibited the aminoacylation activity of recombinant ChPheRS. Medicinal chemistry optimization led to the identification of an optimal pharmacokinetic/pharmacodynamic profile for this series. Collectively, these data demonstrate that bicyclic azetidines are a promising series for anticryptosporidial drug development and establish a broad framework to enable target-based drug discovery for this infectious disease.
Original languageEnglish (US)
Pages (from-to)eaba8412
JournalScience Translational Medicine
Volume12
Issue number563
DOIs
StatePublished - Sep 30 2020

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