Swann, Justine, plouffe, David, Winzeler, Elizabeth and Meister, Stephan (2016) A high-­‐throughput luciferase-­‐based assay for the discovery of therapeutics that prevent malaria. ACS Infectious Diseases.

Abstract

In order to identify the most attractive starting points for drugs that can be used to prevent malaria, a diverse chemical space comprised of 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 optimized for a 1536 well format. This assay uses 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 parasite blood stage parasites and a set of 9,900 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 activity of less than 1 µM with minimal host cell toxicity. Our data demonstrate the utility of this method to identify scaffold families that are known to have causal prophylactic activity in both human and animal models of malaria, as well as novel compounds, including some with activity only against parasite exoerythrocytic stages.

Item Type:	Article
Date Deposited:	27 Apr 2016 23:45
Last Modified:	27 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/27579