4.
Prakash O, Führing J, Post J, Shepherd SM, Eadsforth TC, Gray D, Fedorov R, Routier FH.
Molecules. 2019 Mar 12;24(5). pii: E996. doi: 10.3390/molecules24050996.
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.Free PMC Article
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