Double drugging of prolyl-tRNA synthetase provides a new paradigm for anti-infective drug development

• DOI: 10.1371/journal.ppat.1010363
• Publication Date: 2022-03-25T17:47:33Z
• Authors: Yogavel Manickam; Nipun Malhotra; Siddhartha Mishra; Palak Babbar; Abhishek Dusane; Benoît Laleu; Valeria Bellini; Mohamed-Ali Hakimi; Alexandre Bougdour; Amit Sharma
• Keywords: Druggability

Toxoplasmosis is caused by Toxoplasma gondii and in immunocompromised patients it may lead to seizures, encephalitis or death. The conserved enzyme prolyl-tRNA synthetase (PRS) a validated druggable target but the traditional 'single target-single drug' approach has its caveats. Here, we describe two potent inhibitors namely halofuginone (HFG) novel ATP mimetic (L95) that bind PRS simultaneously at different neighbouring sites cover all three of substrate subsites. HFG L95 act as one triple-site inhibitor tandem form an unusual ternary complex wherein occupies 3'-end tRNA L-proline (L-pro) binding while pocket. These exhibit nanomolar IC50 EC50 values independently, when given together reveal additive mode action parasite inhibition assays. This work validates lays structural framework for further drug development based on simultaneous targeting multiple pockets inhibit proteins.