Nakahara Hiroki, Sennari Goh, Azami Haruki, Tsutsumi Hayama, Watanabe Yoshihiro, Noguchi Yoshihiko, Inahashi Yuki, Iwatsuki Masato, Hirose Tomoyasu, Sunazuka Toshiaki
Ōmura Satoshi Memorial Institute, Graduate School of Infection Control Sciences, Kitasato University 5-9-1 Shirokane, Minato-ku Tokyo 108-8641 Japan
Chem Sci. 2025 Mar 4;16(14):6060-6069. doi: 10.1039/d5sc00566c. eCollection 2025 Apr 2.
Macrocyclic peptides, including depsipeptides, are an emerging new modality in drug discovery research. Tetraselide, an antifungal cyclic peptide isolated from a marine-derived filamentous fungus, possesses a unique amphiphilic structural feature consisting of five consecutive β-hydroxy-amino acid residues and fatty acid moieties. Because the structure elucidation of the naturally occurring product left six stereocenters ambiguous, we implemented bioinformatic analyses, chemical degradation studies and chiral pool fragment synthesis to identify two of the undetermined stereocenters. Convergent total synthesis of the four remaining plausible isomers of tetraselide was accomplished liquid-phase peptide synthesis (LPPS) using soluble hydrophobic tag auxiliaries. The key advances involve fragment coupling by the serine/threonine ligation (STL) reaction and head-to-tail macrolactamization of the carrier-supported precursors that enabled systematic elaboration of the amphiphilic cyclic peptides. Ultimately, we determined the absolute structure of this natural product.
大环肽，包括缩肽，是药物发现研究中一种新兴的新模式。四塞利德是一种从海洋丝状真菌中分离出的抗真菌环肽，具有独特的两亲性结构特征，由五个连续的β-羟基氨基酸残基和脂肪酸部分组成。由于天然产物的结构解析使六个立体中心不明确，我们进行了生物信息学分析、化学降解研究和手性池片段合成，以确定两个未确定的立体中心。使用可溶性疏水标签辅助剂，通过液相肽合成（LPPS）完成了四塞利德其余四种可能异构体的汇聚全合成。关键进展包括通过丝氨酸/苏氨酸连接（STL）反应进行片段偶联以及载体支持的前体的头尾大环化，这使得能够系统地构建两亲性环肽。最终，我们确定了这种天然产物的绝对结构。
