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.
Highlights
Leishmaniasis, categorized as a "Neglected Tropical Disease by WHO, affects about 12 million people worldwide and is often related to poverty [1]
The available treatment options for leishmaniasis are limited to pentavalent antimonials, amphotericin B, miltefosine, paromomycin, sitamaquine, pentamidine, or a combination of these drugs when resistance is reported
Biosynthesis of uridine diphosphate-glucose (UDP-Glc) and/or UDP-Gal by Leishmania promastigotes is essential for parasite growth and survival in vitro [37]
Summary
Leishmaniasis, categorized as a "Neglected Tropical Disease by WHO, affects about 12 million people worldwide and is often related to poverty [1]. The causative agents of this disease are protozoan flagellates of the genus Leishmania, and there are over 20 different species that are reported to cause this disease in humans, as well as in various synanthropic animal hosts [2]. Leishmania species and the immune status of the host, clinical manifestation can vary from disfiguring cutaneous or mucocutaneous forms, to a life-threatening visceral form [3,4]. The mortality due to visceral leishmaniasis has decreased from approximately 62,000 to 14,000 casualties between 2013 and. No vaccines are available against this disease [7]. Growing concern over reports of drug resistance and adverse effects
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
