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

DOI: 10.1371/journal.ppat.1010363

Authors: Yogavel Manickam (International Centre for International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Nipun Malhotra (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Siddhartha Mishra (International Centre for Genetic Engineering and Biotechnology (ICGEB); ICMR-National Institute of Malaria Research (NIMR); Academy of Scientific and Innovative Research (AcSIR)) , Palak Babbar (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Abhishek Dusane (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Benoît Laleu (Medicines for Malaria Venture (MMV), International Center Cointrin (ICC)) , Valeria Bellini (NSERM U1209, CNRS UMR5309, Université Grenoble Alpes) , Mohamed-Ali Hakimi (NSERM U1209, CNRS UMR5309, Université Grenoble Alpes) , Alexandre Bougdour (NSERM U1209, CNRS UMR5309, Université Grenoble Alpes) , Amit Sharma (International Centre for Genetic Engineering and Biotechnology (ICGEB); ICMR-National Institute of Malaria Research (NIMR); Academy of Scientific and Innovative Research (AcSIR))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos Pathogens , VOL 18

State: Published (Approved)
Published: March 2022
Diamond Proposal Number(s): 19946

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

Journal Keywords: Enzyme inhibitors; Toxoplasma gondii; Parasitic diseases; Drug interactions; Enzymes; Transfer RNA; Drug research and development; Toxoplasmosis

Diamond Keywords: Toxoplasmosis; Enzymes

Subject Areas: Biology and Bio-materials, Mathematics


Instruments: I03-Macromolecular Crystallography

Added On: 28/03/2022 10:42

Documents:
journal.ppat.1010363.pdf

Discipline Tags:

Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)