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

Min Jin Kang, Tongde Wu, E. M Kithsiri Wijeratne, Eric C. Lau, Damian J. Mason, Celestina Mesa, Joseph Tillotson, Donna Zhang, Leslie Gunatilaka, James J. La Clair, Eli Chapman

Research output: Contribution to journalArticle

17 Scopus citations

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. Picking p97's pockets: Functional chromatography was used to identify natural products that bind to p97. Application of this method to a panel of fungal and plant extracts identified rheoemodin, 1-hydroxy-dehydroherbarin, and phomapyrrolidinone A, each with a unique mechanism of p97 modulation. This strongly supports the application of functional chromatography to discover discrete protein modulators.

Original languageEnglish (US)
Pages (from-to)2125-2131
Number of pages7
JournalChemBioChem
Volume16
Issue number17
DOIs
Publication statusPublished - 2014

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Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology

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