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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12

AUTHORS

Jennifer L. Norcliffe, John G. Mina, Emilio Alvarez, Juan Cantizani, Francisco de Dios-Anton, Gonzalo Colmenarejo, Silva Gonzalez-Del Valle, Maria Marco, José M. Fiandor, Julio J. Martin, Patrick G. Steel, Paul W. Denny

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. More... »

PAGES

3938

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-018-22063-9

DOI

http://dx.doi.org/10.1038/s41598-018-22063-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1101225828

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29500420


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