Tuesday, September 05, 2017

Targeting Prolyl-tRNA Synthetase

2017 Aug 24. pii: S0969-2126(17)30249-6. doi: 10.1016/j.str.2017.07.015. [Epub ahead of print]

Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis

Jain V¹, Yogavel M¹, Kikuchi H², Oshima Y², Hariguchi N³, Matsumoto M⁴, Goel P¹, Touquet B⁵, Jumani RS⁶, Tacchini-Cottier F⁷, Harlos K⁸, Huston CD⁶, Hakimi MA⁵, Sharma A⁹.

Developing anti-parasitic lead compounds that act on key vulnerabilities are necessary for new anti-infectives. Malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis and coccidiosis together kill >500,000 humans annually. Their causative parasites Plasmodium, Leishmania, Toxoplasma, Cryptosporidium and Eimeria display high conservation in many housekeeping genes, suggesting that these parasites can be attacked by targeting invariant essential proteins. Here, we describe selective and potent inhibition of prolyl-tRNA synthetases (PRSs) from the above parasites using a series of quinazolinone-scaffold compounds. Our PRS-drug co-crystal structures reveal remarkable active site plasticity that accommodates diversely substituted compounds, an enzymatic feature that can be leveraged for refining drug-like properties of quinazolinones on a per parasite basis. A compound we termed In-5 exhibited a unique double conformation, enhanced drug-like properties, and cleared malaria in mice. It thus represents a new lead for optimization. Collectively, our data offer insights into the structure-guided optimization of quinazolinone-based compounds for drug development against multiple human eukaryotic pathogens.