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High-Throughput Luciferase-Based Assay for the Discovery of Therapeutics That Prevent Malaria.

Abstract：

:In order to identify the most attractive starting points for drugs that can be used to prevent malaria, a diverse chemical space comprising tens of thousands to millions of small molecules may need to be examined. Achieving this throughput necessitates the development of efficient ultra-high-throughput screening methods. Here, we report the development and evaluation of a luciferase-based phenotypic screen of malaria exoerythrocytic-stage parasites optimized for a 1536-well format. This assay uses the exoerythrocytic stage of the rodent malaria parasite, Plasmodium berghei, and a human hepatoma cell line. We use this assay to evaluate several biased and unbiased compound libraries, including two small sets of molecules (400 and 89 compounds, respectively) with known activity against malaria erythrocytic-stage parasites and a set of 9886 diversity-oriented synthesis (DOS)-derived compounds. Of the compounds screened, we obtain hit rates of 12-13 and 0.6% in preselected and naïve libraries, respectively, and identify 52 compounds with exoerythrocytic-stage activity less than 1 μM and having minimal host cell toxicity. Our data demonstrate the ability of this method to identify compounds known to have causal prophylactic activity in both human and animal models of malaria, as well as novel compounds, including some exclusively active against parasite exoerythrocytic stages.

journal_name

ACS Infect Dis

journal_title

ACS infectious diseases

authors

Swann J,Corey V,Scherer CA,Kato N,Comer E,Maetani M,Antonova-Koch Y,Reimer C,Gagaring K,Ibanez M,Plouffe D,Zeeman AM,Kocken CH,McNamara CW,Schreiber SL,Campo B,Winzeler EA,Meister S

doi

10.1021/acsinfecdis.5b00143

subject

Has Abstract

pub_date

2016-04-08 00:00:00

pages

281-293

issue

4

issn

2373-8227

journal_volume

2

pub_type

杂志文章

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