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.
journal_name
Sci Repjournal_title
Scientific reportsauthors
Norcliffe JL,Mina JG,Alvarez E,Cantizani J,de Dios-Anton F,Colmenarejo G,Valle SG,Marco M,Fiandor JM,Martin JJ,Steel PG,Denny PWdoi
10.1038/s41598-018-22063-9subject
Has Abstractpub_date
2018-03-02 00:00:00pages
3938issue
1issn
2045-2322pii
10.1038/s41598-018-22063-9journal_volume
8pub_type
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