Chemical Validation of Methionyl tRNA Synthetase (MetRS) as a Druggable Target in Leishmania donovani

Leah Torrie, Stephen Brand, David Robinson, Eun Jung Ko, Laste Stojanovski, Frederick R. C. Simeons, Susan Wyllie, John Thomas, Lucy Ellis, Maria Osuna-Cabello, Rafiu Epemolu, Andrea Nuehs, Jennifer Riley, Lorna MacLean, Sujatha Manthri, Kevin Read, Ian Gilbert (Lead / Corresponding author), Alan Fairlamb, Manu De Rycker (Lead / Corresponding author)

Research output: Contribution to journalArticle

7 Citations (Scopus)
156 Downloads (Pure)

Abstract

Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. In the present study we investigate the validity of this target in the related trypanosomatid Leishmania donovani. Following development of a robust highthroughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki 18 nM). Crystallography revealed this compound binds to the methionine pocket of MetRS with enzymatic studies confirming DDD806905 displays competitive inhibition with respect to methionine and mixed inhibition with respect to ATP binding. DDD806905 showed activity, albeit with different levels of potency, in various Leishmania cell-based viability assays, with on-target activity observed in both Leishmania promastigote cell assays and a Leishmania tarentolae in vitro translation assay. Unfortunately this compound failed to show efficacy in an animal model of leishmaniasis. We investigated the potential causes for the discrepancies in activity observed in different Leishmania cell assays and the lack of efficacy in the animal model and found that high protein binding as well as sequestration of this dibasic compound into acidic compartments may play a role. Despite medicinal chemistry efforts to address the dibasic nature of DDD806905 and analogues, no progress could be achieved with the current chemical series. Although DDD806905 is not a developable anti-leishmanial compound, MetRS remains an attractive anti-leishmanial drug target.
Original languageEnglish
Pages (from-to)718-727
Number of pages10
JournalACS Infectious Diseases
Volume3
Issue number10
Early online date2 Oct 2017
DOIs
Publication statusPublished - Oct 2017

Keywords

  • Drug Discovery
  • Kinetoplastids
  • Translation
  • tRNA synthetase
  • Parasite

Fingerprint Dive into the research topics of 'Chemical Validation of Methionyl tRNA Synthetase (MetRS) as a Druggable Target in <i>Leishmania donovani</i>'. Together they form a unique fingerprint.

  • Projects

    Profiles

    Cite this