Diversity-oriented synthesis yields novel multistage antimalarial inhibitors
Publication Type:
Journal Article
Authors:
Kato†, Nobutaka; Comer, Eamon†; Sakata-Kato, Tomoyo; Sharma, Arvind; Sharma, Manmohan; Maetani, Micah; Bastien, Jessica; Brancucci, Nicolas M.; Bittker, Joshua A.; Corey, Victoria; Clarke, David; Derbyshire, Emily R.; Dornan, Gillian; Duffy, Sandra; Eckley, Sean; Itoe, Maurice A.; Koolen, Karin M J; Lewis, Timothy A.; Lui, Ping S.; Lukens, Amanda K.; Lund, Emily; March, Sandra; Meibalan, Elamaran; Meier, Bennett C.; McPhail, Jacob; Mitasev, Branko; Moss, Eli L.; Sayes, Morgane; VanGessel, Yvonne; Wawer, Mathias J.; Yoshinaga, Takashi; Zeeman, Anne-Marie; Avery, Vicky M.; Bhatia, Sangeeta N.; Burke, John E.; Catteruccia, Flaminia; Clardy, Jon C.; Clemons, Paul A.; Dechering, Koen J.; Duvall, Jeremy R.; Foley, Michael A.; Gusovsky, Fabian; Kocken, Clemens H. M.; Marti, Matthias; Morningstar, Marshall L.; Munoz, Benito; Neafsey, Daniel E.; Sharma, Amit; Winzeler, Elizabeth A.; Wirth, Dyann F.; Scherer, Christina A.; Schreiber, Stuart L.
Source:
Nature, Volume 538, Issue 7625, p.344-349 (2016)
URL:
http://www.nature.com/doifinder/10.1038/nature19804
Abstract:
Antimalarial drugs have thus far been derived mainly from two sources - natural products and synthetic "drug-like" compounds. We hypothesized that antimalarial agents with novel mechanisms of action might be discovered using a diverse collection of synthetic compounds having three-dimensional features reminiscent of natural products and underrepresented in typical screening collections. We identified such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. The bicylic azetidines display single low-dose cure with activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to cure and prevent transmission of the disease as well as protect populations at risk, all in a single oral exposure, and highlight the strength of diversity-oriented synthesis to reveal promising therapeutic targets.
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