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Chembiochem. 2014 Sep 22;15(14):2125-31. doi: 10.1002/cbic.201402258. Epub 2014 Aug 14.

Functional chromatography reveals three natural products that target the same protein with distinct mechanisms of action.

Author information

1
College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721-0207 USA).

Abstract

Access to lead compounds with defined molecular targets continues to be a barrier to the translation of natural product resources. As a solution, we developed a system that uses discrete, recombinant proteins as the vehicles for natural product isolation. Here, we describe the use of this functional chromatographic method to identify natural products that bind to the AAA+ chaperone, p97, a promising cancer target. Application of this method to a panel of fungal and plant extracts identified rheoemodin, 1-hydroxydehydroherbarin, and phomapyrrolidone A as distinct p97 modulators. Excitingly, each of these molecules displayed a unique mechanism of p97 modulation. This discovery provides strong support for the application of functional chromatography to the discovery of protein modulators that would likely escape traditional high-throughput or phenotypic screening platforms.

KEYWORDS:

AAA+; ATPase; drug discovery; natural products; p97/VCP/Cdc48

PMID:
25125376
PMCID:
PMC4187115
DOI:
10.1002/cbic.201402258
[Indexed for MEDLINE]
Free PMC Article

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