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Identification of Leishmania major UDP-Sugar Pyrophosphorylase Inhibitors Using Biosensor-Based Small Molecule Fragment Library Screening

1
Department of Clinical Biochemistry OE4340, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
2
School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
3
Institute for Biophysical Chemistry, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Lothar Elling
Molecules 2019, 24(5), 996; https://doi.org/10.3390/molecules24050996
Received: 29 January 2019 / Revised: 4 March 2019 / Accepted: 7 March 2019 / Published: 12 March 2019
(This article belongs to the Special Issue Synthesis and Biological Applications of Glycoconjugates Ⅱ)
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Abstract

Leishmaniasis is a neglected disease that is caused by different species of the protozoan parasite Leishmania, and it currently affects 12 million people worldwide. The antileishmanial therapeutic arsenal remains very limited in number and efficacy, and there is no vaccine for this parasitic disease. One pathway that has been genetically validated as an antileishmanial drug target is the biosynthesis of uridine diphosphate-glucose (UDP-Glc), and its direct derivative UDP-galactose (UDP-Gal). De novo biosynthesis of these two nucleotide sugars is controlled by the specific UDP-glucose pyrophosphorylase (UGP). Leishmania parasites additionally express a UDP-sugar pyrophosphorylase (USP) responsible for monosaccharides salvage that is able to generate both UDP-Gal and UDP-Glc. The inactivation of the two parasite pyrophosphorylases UGP and USP, results in parasite death. The present study reports on the identification of structurally diverse scaffolds for the development of USP inhibitors by fragment library screening. Based on this screening, we selected a small set of commercially available compounds, and identified molecules that inhibit both Leishmania major USP and UGP, with a half-maximal inhibitory concentration in the 100 µM range. The inhibitors were predicted to bind at allosteric regulation sites, which were validated by mutagenesis studies. This study sets the stage for the development of potent USP inhibitors. View Full-Text
Keywords: UDP-sugar pyrophosphorylase; allosteric inhibitor; inhibitor scaffold; library screen UDP-sugar pyrophosphorylase; allosteric inhibitor; inhibitor scaffold; library screen
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Prakash, O.; Führing, J.; Post, J.; Shepherd, S.M.; Eadsforth, T.C.; Gray, D.; Fedorov, R.; Routier, F.H. Identification of Leishmania major UDP-Sugar Pyrophosphorylase Inhibitors Using Biosensor-Based Small Molecule Fragment Library Screening. Molecules 2019, 24, 996.

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