title: Total synthesis and anti-hepatitis C virus activity of MA026.
abstract: The first total synthesis of MA026 and the identification of its candidate target protein for anti-hepatitis C virus activity are presented. MA026, a novel lipocyclodepsipeptide isolated from the fermentation broth of Pseudomonas sp. RtIB026, consists of a cyclodepsipeptide, a chain peptide, and an N-terminal (R)-3-hydroxydecanoic acid. The first subunit, side chain 2, was prepared by coupling fatty acid moiety 4 with tripeptide 5. The key macrocyclization of the decadepsipeptide at L-Leu(10)-D-Gln(11) provided the second subunit, cyclodepsipeptide 3. Late-stage condensation of the two key subunits and final deprotection afforded MA026. This convergent, flexible, solution-phase synthesis will be invaluable in generating MA026 derivatives for future structure-activity relationship studies. An infectious hepatitis C virus (HCV) cell culture assay revealed that MA026 suppresses HCV infection into host hepatocytes by inhibiting the entry process in a dose-dependent manner. Phage display screening followed by surface plasmon resonance (SPR) binding analyses identified claudin-1, an HCV entry receptor, as a candidate target protein of MA026.
authors.affiliation: Department of Applied Biological Science, Tokyo University of Sciences , Noda, Chiba 278-8510, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Shimura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ishima
authors.forename: Syo
authors.initials: S
authors.lastname: Nakajima
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Fujii
authors.forename: Natsumi
authors.initials: N
authors.lastname: Himeno
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ikeda
authors.forename: Jesus
authors.initials: J
authors.lastname: Izaguirre-Carbonell
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Murata
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Kamisuki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kouji
authors.initials: K
authors.lastname: Kuramochi
authors.forename: Koichi
authors.initials: K
authors.lastname: Watashi
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D005285:Fermentation; D016174:Hepacivirus / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D047630:Depsipeptides; C000590314:MA026 compound