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Double drugging of prolyl-tRNA synthetase provides a new paradigm for anti-infective drug development
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Double drugging of prolyl-tRNA synthetase provides a new paradigm for anti-infective drug development
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Journal Article
Double drugging of prolyl-tRNA synthetase provides a new paradigm for anti-infective drug development
2022
Overview
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 IC 50 and EC 50 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.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
Adenosine Triphosphate - metabolism
/ Amino Acyl-tRNA Synthetases - chemistry
/ Amino Acyl-tRNA Synthetases - metabolism
/ Antiinfectives and antibacterials
/ ATP
/ Biochemistry, Molecular Biology
/ Enzymes
/ Humans
/ Ligands
/ Malaria
/ Medicine and Health Sciences
/ Microbiology and Parasitology
/ Proline
/ Proteins
/ Seizures
/ tRNA Pro
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