title: Functional chromatography reveals three natural products that target the same protein with distinct mechanisms of action.
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.
authors.affiliation: College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721-0207 USA).
authors.forename: Min Jin
authors.initials: MJ
authors.lastname: Kang
authors.forename: Tongde
authors.initials: T
authors.lastname: Wu
authors.forename: E M Kithsiri
authors.initials: EM
authors.lastname: Wijeratne
authors.forename: Eric C
authors.initials: EC
authors.lastname: Lau
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Mason
authors.forename: Celestina
authors.initials: C
authors.lastname: Mesa
authors.forename: Joseph
authors.initials: J
authors.lastname: Tillotson
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
authors.forename: A A Leslie
authors.initials: AA
authors.lastname: Gunatilaka
authors.forename: James J
authors.initials: JJ
authors.lastname: La Clair
authors.forename: Eli
authors.initials: E
authors.lastname: Chapman
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002845:Chromatography / Q000379:methods; D055808:Drug Discovery / Q000379:methods; D005658:Fungi / Q000737:chemistry; D006801:Humans; D009285:Naphthoquinones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D010944:Plants / Q000737:chemistry
chemical_list: C525428:1-hydroxydehydroherbarin; D000470:Alkaloids; D001688:Biological Products; D009285:Naphthoquinones; D009687:Nuclear Proteins; C585304:phomapyrrolidone A; D000251:Adenosine Triphosphatases; C404942:p97 ATPase
keywords: AAA+; ATPase; drug discovery; natural products; p97/VCP/Cdc48