Total Synthesis and Anti-Hepatitis C Virus Activity of MA026

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• 作者：Satomi Shimura ; Masahiro Ishima ; Syo Nakajima ; Toshitaka Fujii ; Natsumi Himeno ; Kentaro Ikeda ; Jesus Izaguirre-Carbonell ; Hiroshi Murata ; Toshifumi Takeuchi ; Shinji Kamisuki ; Takahiro Suzuki ; Kouji Kuramochi ; Koichi Watashi ; Susumu Kobayashi ; Fumio Sugawara
• 刊名：Journal of the American Chemical Society
• 出版年：2013
• 出版时间：December 18, 2013
• 年：2013
• 卷：135
• 期：50
• 页码：18949-18956
• 全文大小：522K
• 年卷期：v.135,no.50(December 18, 2013)
• ISSN：1520-5126

文摘

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-Leu¹⁰-d-Gln¹¹ 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鈥揳ctivity 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.