Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

  • Journal Article

Journal:
Nature, Volume: 538, Issue: 7625
Published:
October 20, 2016
PMID:
27602946
Authors:
Nobutaka Kato N, Eamon Comer E, Tomoyo Sakata-Kato T, Arvind Sharma A, Manmohan Sharma M, Micah Maetani M, Jessica Bastien J, Nicolas M Brancucci NM, Joshua A Bittker JA, Victoria Corey V, David Clarke D, Emily R Derbyshire ER, Gillian L Dornan GL, Sandra Duffy S, Sean Eckley S, Maurice A Itoe MA, Karin M J Koolen KM, Timothy A Lewis TA, Ping S Lui PS, Amanda K Lukens AK, Emily Lund E, Sandra March S, Elamaran Meibalan E, Bennett C Meier BC, Jacob A McPhail JA, Branko Mitasev B, Eli L Moss EL, Morgane Sayes M, Yvonne Van Gessel Y, Mathias J Wawer MJ, Takashi Yoshinaga T, Anne-Marie Zeeman AM, Vicky M Avery VM, Sangeeta N Bhatia SN, John E Burke JE, Flaminia Catteruccia F, Jon C Clardy JC, Paul A Clemons PA, Koen J Dechering KJ, Jeremy R Duvall JR, Michael A Foley MA, Fabian Gusovsky F, Clemens H M Kocken CH, Matthias Marti M, Marshall L Morningstar ML, Benito Munoz B, Daniel E Neafsey DE, Amit Sharma A, Elizabeth A Winzeler EA, Dyann F Wirth DF, Christina A Scherer CA, Stuart L Schreiber SL
Abstract:

Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of 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. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.