Research ArticleInfectious Disease

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

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Science Translational Medicine  30 Sep 2020:
Vol. 12, Issue 563, eaba8412
DOI: 10.1126/scitranslmed.aba8412

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An antimalarial lead gets a new target

Cryptosporidiosis, a parasitic intestinal infection caused by Cryptosporidium, is particularly problematic in children and the immunocompromised yet lacks effective therapies. Bicyclic azetidines have previously been shown to target malaria-causing Plasmodium falciparum via its phenylalanyl-tRNA synthetase (PheRS). Vinayak et al. now extend these findings, showing that this series of compounds can target two common strains of Cryptosporidium, which, like P. falciparum, is an apicomplexan parasite. Optimized bicyclic azetidines showed efficacy against Cryptosporidium in vitro and in an immunocompromised mouse model of established cryptosporidiosis, and mutation studies confirmed that the mechanism of action involved PheRS. These compounds may have potential in treating cryptosporidiosis in humans.

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