Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy

Abstract

Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5′-monophosphate–mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid–sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5′-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum , namely tyrosine RS ( Pf YRS). ML901 exerts whole-life-cycle–killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.

Anti-Phytophthora Activity of Halofuginone and the Corresponding Mode of Action

“…These enzymes are housekeeping enzymes that have essential roles in proteostasis and are considered attractive drug targets in pathogenic organisms. ,, For example, mupirocin and tavaborole, which are inhibitors of isoleucyl-tRNA synthetase and leucyl-tRNA synthetase, respectively, have been marketed for the topical treatment of methicillin-resistant Staphylococcus aureus infections and onychomycosis . Some other compounds, such as cladosporin, mL901, and borrelidin, which target lysyl-tRNA synthetase, tyrosyl-tRNA synthetase, and threonyl-tRNA synthetase, respectively, are also attractive candidate therapeutic agents. − However, except for borrelidin (which was described as a potential antifungal agent against P. sojae), the inhibitors that target aminoacyl-tRNA synthetases and are used as pesticides are seldom reported .…”

The pathophyiological role of aminoacyl-tRNA synthetases in digestive system diseases

“…Several ARSs inhibitors have been applied in the clinical practice including the IRS inhibitor anti-bacterial mupirocin, for the treatment of topical infections caused by G-positive bacteria ( Pappa, 1990 ; Nakama et al, 2001 ), the LRS inhibitor anti-fungal AN2690, for the treatment of onychomycosis which is caused by dermatophytes ( Rock et al, 2007 ), and the PRS inhibitor anti-protozoal halofuginone, for the treatment of malaria ( Samant and Sukhthankar, 2009 ). Moreover, the YRS inhibitor ML901, exhibits whole-life-cycle killing activity in a mouse model of malaria ( Xie et al, 2022 ), and the LRS inhibitor GSK656, has been used in clinical trials for systemic use against tuberculosis ( Tenero et al, 2019 ). Since ARSs are essential enzymes both in humans and pathogens such as bacteria, fungus, and parasites, it is important for antimicrobial drugs to exhibit toxicity against the targeted organism while leave the human physiology unaffected.…”

Keystone Malaria Symposium 2022: a vibrant discussion of progress made and challenges ahead from drug discovery to treatment

“…Dr Leann Tilley (University of Melbourne) presented work on a nucleoside sulfamate, ML901, that has a novel P. falciparum tyrosine tRNA synthetase target. These nucleoside sulfamates have a new inhibition mechanism, whereby a highly potent inhibitor is generated at the site of action [21]. Preparing for the possibility of ART resistance spreading through Africa, Dr Colin Sutherland (London School of Hygiene & Tropical Medicine) proposed active testing of alternative treatment strategies using current drugs, such as sequential ACT regimens.…”