We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Bicyclic azetidines kill the diarrheal pathogen Cryptosporidium in mice by inhibiting parasite phenylalanyl-tRNA synthetase.
- Authors
Vinayak, Sumiti; Jumani, Rajiv S.; Miller, Peter; Hasan, Muhammad M.; McLeod, Briana I.; Tandel, Jayesh; Stebbins, Erin E.; Teixeira, Jose E.; Borrel, Julien; Gonse, Arthur; Zhang, Mingliang; Yu, Xianshui; Wernimont, Amy; Walpole, Chris; Eckley, Sean; Love, Melissa S.; McNamara, Case W.; Sharma, Manmohan; Sharma, Amit; Scherer, Christina A.
- Abstract
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. 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.
- Subjects
CRYPTOSPORIDIUM; CHAGAS' disease; CRYPTOSPORIDIUM parvum; PARASITIC diseases; PARASITES; INTESTINAL infections; COMMUNICABLE diseases
- Publication
Science Translational Medicine, 2020, Vol 12, Issue 563, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aba8412