Department of Applied Biological Science, Tokyo University of Sciences , Noda, Chiba 278-8510, Japan.
J Am Chem Soc. 2013 Dec 18;135(50):18949-56. doi: 10.1021/ja410145x. Epub 2013 Dec 6.
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.
首次全合成 MA026 并鉴定其抗丙型肝炎病毒活性的候选靶蛋白。MA026 是一种新型脂环环二肽，从假单胞菌 RtIB026 的发酵液中分离得到，由环二肽、链肽和 N-端（R）-3-羟基癸酸组成。第一个亚基，侧链 2，通过将脂肪酸部分 4 与三肽 5 偶联制备。在 L-Leu（10）-D-Gln（11）处的十肽进行大环化提供了第二个亚基，环二肽 3。两个关键亚基的后期缩合和最终脱保护得到 MA026。这种收敛、灵活、溶液相合成将在生成 MA026 衍生物以进行未来的结构-活性关系研究中非常有价值。一种感染性丙型肝炎病毒（HCV）细胞培养测定表明，MA026 通过抑制进入过程以剂量依赖的方式抑制 HCV 感染进入宿主肝细胞，从而抑制 HCV 感染。噬菌体展示筛选随后进行表面等离子体共振（SPR）结合分析，鉴定出紧密连接蛋白-1（Claudin-1），一种 HCV 进入受体，为 MA026 的候选靶蛋白。
