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Proc Natl Acad Sci U S A. 2019 May 7;116(19):9318-9323. doi: 10.1073/pnas.1820175116. Epub 2019 Apr 8.

Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition.

Author information

1
Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
2
Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
3
Global Health R&D, GlaxoSmithKline, Tres Cantos, 28760, Spain.
4
David Jack Centre for R&D, GlaxoSmithKline, Ware SG12 0DP, United Kingdom.
5
Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom; k.read@dundee.ac.uk maria.m.marco@gsk.com p.g.wyatt@dundee.ac.uk.
6
Global Health R&D, GlaxoSmithKline, Tres Cantos, 28760, Spain; k.read@dundee.ac.uk maria.m.marco@gsk.com p.g.wyatt@dundee.ac.uk.

Abstract

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the β5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the β4 and β5 proteasome subunits. This induced pocket exploits β4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.

KEYWORDS:

Leishmania; cryo-EM; drug discovery; proteasome

Conflict of interest statement

Conflict of interest statement: The following authors have shares in GlaxoSmithKline: C.-w.C., I.P., R.P.B., J.C., D.C., P.D.C., P.G., J. Howe, J.K., M.S.M., L.M-C., S.R., P.R., J.M.F., J.M., D.W.G., T.J.M., K.D.R., M.M., and P.G.W.

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