Chemical validation of methionyl-trna synthetase as a druggable target in Leishmania donovani

DOI: 10.1021/acsinfecdis.7b00047

Authors: Leah S. Torrie (University of Dundee) , Stephen Brand (University of Dundee) , David A. Robinson (University of Dundee) , Eun Jung Ko (University of Dundee) , Laste Stojanovski (University of Dundee) , Frederick R. C. Simeons (University of Dundee) , Susan Wyllie (University of Dundee) , John Thomas (University of Dundee) , Lucy Ellis (University of Dundee) , Maria Osuna-Cabello (University of Dundee) , Ola Epemolu (University of Dundee) , Andrea Nühs (University of Dundee) , Jennifer Riley (University of Dundee) , Lorna Maclean (University of Dundee) , Sujatha Manthri (University of Dundee) , Kevin D. Read (University of Dundee) , Ian H. Gilbert (University of Dundee) , Alan H. Fairlamb (University of Dundee) , Manu De Rycker (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Infectious Diseases

State: Published (Approved)
Published: October 2017
Diamond Proposal Number(s): 8268

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 high-throughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki of 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 antileishmanial compound, MetRS remains an attractive antileishmanial drug target.

Journal Keywords: drug discovery; kinetoplastids; parasite; translation; tRNA synthetase

Diamond Keywords: Leishmaniasis; Enzymes

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 09/10/2017 10:03

Documents:
acsin5656fecdis.pdf

Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)