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发布日期: Jul 17, 2019
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Development of a target-free high throughput screening platform for the discovery of anti-leishmanial compounds - ScienceDirect

Highlights.•Developed a simple fluorometric and target-free method for primary drug screening•2,4-diaminoquinazoline scaffold has activity against two species of Leishmania•Scaffold exhibits varying selectivity against target cells in vitro and in vivo•Scaffold appropriate for cutaneous leishmaniasis and topical development.Abstract.Leishmania parasites are the causative agents of a wide spectrum of human diseases. The clinical manifestations of leishmaniasis range from self-healing skin lesions to fatality. The WHO has declared leishmaniasis a Category I Neglected Tropical Disease. This disease represents a major international health challenge, affecting 12 million people per year and with nearly 310 million people at risk. The first-line chemotherapies used to treat leishmaniasis are intravenous pentavalent antimonials; however, these drugs are highly toxic. Oral treatment options such as paromomycin and miltefosine have been used more as incidences of disease relapse and drug resistance to antimonials develop, emphasizing the importance of identifying new chemotherapies. We developed a novel, target-free fluorometric high-throughput screen (HTS), with an average Z-score of 0.73 +/- 0.13, to identify small molecules with anti-leishmanial activity. Screening of 10,000 small molecules from the ChemBridge DIVER-set™ library cassette #5 yielded 210 compounds that killed 80 percent of parasites, resulting in a hit rate of 2.1 percent. One hundred nine (109) molecular scaffolds were represented within the hit compounds; one scaffold that exhibits potent anti-leishmanial activity was 2,4-diaminoquinazoline (2,4-DAQ). Host cell toxicity was determined prior to in vitro infection of human THP-1 macrophages with L. donovani mCherry expressing promastigotes; successful drug treatment was considered when the IC50 was less than 10μM. BALB/C mice were infected with L. major mCherry promastigotes and treated with small molecules that were successful during in vitro infections. Several small molecules tested were equally efficacious at resolving CL lesions in mice as known antimonial treatments.Graphical abstract. Download high-res image (121KB) .Download full-size image .