NDLI: Identifying inhibitors of the Leishmania inositol phosphorylceramide synthase with antiprotozoal activity using a yeast-based assay and ultra-high throughput screening platform

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Identifying inhibitors of the Leishmania inositol phosphorylceramide synthase with antiprotozoal activity using a yeast-based assay and ultra-high throughput screening platform

Content Provider	Semantic Scholar
Author	Norcliffe, Jennifer L. Mina, John G. Álvarez, Emilio Osorio Cantizani, Juan Dios-Anton, Francisco De Colmenarejo, Gonzalo Valle, Silva Gonzalez-Del Marco, Maria Fiandor, José María Martín, Julio J. Steel, Patrick G. Denny, Paul W.
Copyright Year	2018
Abstract	Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the world's poorest, however vaccines are absent and drug therapy limited. Recently, public-private partnerships have developed to identify new modes of controlling leishmaniasis. Drug discovery is a significant part of these efforts and here we describe the development and utilization of a novel assay to identify antiprotozoal inhibitors of the Leishmania enzyme, inositol phosphorylceramide (IPC) synthase. IPC synthase is a membrane-bound protein with multiple transmembrane domains, meaning that a conventional in vitro assay using purified protein in solution is highly challenging. Therefore, we utilized Saccharomyces cerevisiae as a vehicle to facilitate ultra-high throughput screening of 1.8 million compounds. Antileishmanial benzazepanes were identified and shown to inhibit the enzyme at nanomolar concentrations. Further chemistry produced a benzazepane that demonstrated potent and specific inhibition of IPC synthase in the Leishmania cell.
File Format	PDF HTM / HTML
DOI	10.1038/s41598-018-22063-9
PubMed reference number	29500420
Journal	Medline
Volume Number	8
Alternate Webpage(s)	http://dro.dur.ac.uk/24221/1/24221.pdf?DDD7+DDD1+dhs0pwd+nvpw35+nvpw35=
Alternate Webpage(s)	https://ntd-network.org/wp-content/uploads/2018/04/Norcliffe_et_al-2018-Scientific_Reports-copy.pdf
Journal	Scientific Reports
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article

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