Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Kato, N; Comer, E; Sakata-Kato, T; Sharma, A; Sharma, M; Maetani, M; Bastien, J; Brancucci, NM; Bittker, JA; Corey, V; Clarke, D; Derbyshire, ER; Dornan, GL; Duffy, S; Eckley, S; Itoe, MA; Koolen, KMJ; Lewis, TA; Lui, PS; Lukens, AK; Lund, E; March, S; Meibalan, E; Meier, BC; McPhail, JA; Mitasev, B; Moss, EL; Sayes, M; Van Gessel, Y; Wawer, MJ; Yoshinaga, T; Zeeman, A-M; Avery, VM; Bhatia, SN; Burke, JE; Catteruccia, F; Clardy, JC; Clemons, PA; Dechering, KJ; Duvall, JR; Foley, MA; Gusovsky, F; Kocken, CHM; Marti, M; Morningstar, ML; Munoz, B; Neafsey, DE; Sharma, A; Winzeler, EA; Wirth, DF; Scherer, CA; Schreiber, SL
Published Date
- October 2016
Published In
Volume / Issue
- 538 / 7625
Start / End Page
- 344 - 349
PubMed ID
- 27602946
Pubmed Central ID
- PMC5515376
Electronic International Standard Serial Number (EISSN)
- 1476-4687
International Standard Serial Number (ISSN)
- 0028-0836
Digital Object Identifier (DOI)
- 10.1038/nature19804
Language
- eng