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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:
Pathogens
Infectious Diseases
Health & Wellbeing
Structural biology
Drug Discovery
Life Sciences & Biotech
Parasitology
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)