Bicyclic azetidines target acute and chronic stages of Toxoplasma gondii by inhibiting parasite phenylalanyl t-RNA synthetase

Joshua B. Radke, Bruno Melillo, Payal Mittal, Manmohan Sharma, Amit Sharma, Yong Fu, Taher Uddin, Arthur Gonse, Eamon Comer, Stuart L. Schreiber, Anil K. Gupta, Arnab K. Chatterjee and L. David Sibley ()
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Joshua B. Radke: Washington University Sch. Med.
Bruno Melillo: The Scripps Research Institute
Payal Mittal: International Centre for Genetic Engineering and Biotechnology
Manmohan Sharma: International Centre for Genetic Engineering and Biotechnology
Amit Sharma: International Centre for Genetic Engineering and Biotechnology
Yong Fu: Washington University Sch. Med.
Taher Uddin: Washington University Sch. Med.
Arthur Gonse: Broad Institute
Eamon Comer: Broad Institute
Stuart L. Schreiber: Broad Institute
Anil K. Gupta: The Scripps Research Institute
Arnab K. Chatterjee: The Scripps Research Institute
L. David Sibley: Washington University Sch. Med.

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Toxoplasma gondii commonly infects humans and while most infections are controlled by the immune response, currently approved drugs are not capable of clearing chronic infection in humans. Hence, approximately one third of the world’s human population is at risk of reactivation, potentially leading to severe sequelae. To identify new candidates for treating chronic infection, we investigated a series of compounds derived from diversity-oriented synthesis. Bicyclic azetidines are potent low nanomolar inhibitors of phenylalanine tRNA synthetase (PheRS) in T. gondii, with excellent selectivity. Biochemical and genetic studies validate PheRS as the primary target of bicyclic azetidines in T. gondii, providing a structural basis for rational design of improved analogs. Favorable pharmacokinetic properties of a lead compound provide excellent protection from acute infection and partial protection from chronic infection in an immunocompromised mouse model of toxoplasmosis. Collectively, PheRS inhibitors of the bicyclic azetidine series offer promise for treatment of chronic toxoplasmosis.

Date: 2022
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DOI: 10.1038/s41467-022-28108-y

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