Plouffe, David, Wree, Melanie, Du, Alan Y, Li, Fengwu, Patra, Kailash, Lubar, Aristea, Okitsu, Shinji, Flannery, Erika L, Kato, Nobutaka, Tanaseichuk, Olga, Comer, Eamon, Zhou, Bin, Zhou, Yingyao, Leroy, Didier, Schreiber, Stuart L, Dechering, Koen, Sauerwein, Robert, Scherer, Christina A, Vinetz, Joseph and Winzeler, Elizabeth (2016) SaLSSA—a low cost method for assessing the malaria transmission-blocking potential of small molecules. Cell host & microbe, 19 (1). pp. 114-126. ISSN 1934-6069

Abstract

Effective prevention of malaria transmission is an important component of malaria control. However, most methods designed to detect whether a small molecule can block transmission are relatively low throughput and cannot be applied routinely to large chemical libraries nor can they be used to routinely calculate inhibition constants. Here we describe a ultrahigh throughput and cost effective assay, the Saponin-lysis Sexual Stage Assay (SaLSSA), for identifying small molecules that have the capacity to block malaria transmission. In analysis of 13850 compounds our data show that >90% of well characterized and clinically used antimalarial compounds, including endoperoxides and 4-aminoquinolines, as well as compounds discovered by phenotypic screening of asexual blood stages lose most their killing activity as parasites develop into mature, metabolically quiescent stage V gametocytes. On the other hand, our data show that compounds with consistent low nanomolar transmission-blocking activity exist. Similar compounds can be found at a rate of 3% in blood-stage selected libraries and 0.16% in unbiased chemical libraries, including a small diversity-oriented synthesis library. We identify several scaffold families including thioureas and napthoquinones that are active in parasite sexual and asexual stages as well as a few compound classes whose activity is limited to sexual stages. The data highlight the substantial physiological differences between sexual and asexual parasites and provide starting points for altruistic transmission-blocking drugs.

Item Type:	Article
Date Deposited:	12 Oct 2016 00:45
Last Modified:	12 Oct 2016 00:45
URI:	https://oak.novartis.com/id/eprint/26740