Department of Medicinal Chemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.
Angew Chem Int Ed Engl. 2021 Apr 12;60(16):8792-8797. doi: 10.1002/anie.202015193. Epub 2021 Mar 8.
A revised structure of natural 14-mer cyclic depsipeptide MA026, isolated from Pseudomonas sp. RtlB026 in 2002 was established by physicochemical analysis with HPLC, MS/MS, and NMR and confirmed by total solid-phase synthesis. The revised structure differs from that previously reported in that two amino acid residues, assigned in error, have been replaced. Synthesized MA026 with the revised structure showed a tight junction (TJ) opening activity like that of the natural one in a cell-based TJ opening assay. Bioinformatic analysis of the putative MA026 biosynthetic gene cluster (BGC) of RtIB026 demonstrated that the stereochemistry of each amino acid residue in the revised structure can be reasonably explained. Phylogenetic analysis with xantholysin BGC indicates an exceptionally high homology (ca. 90 %) between xantholysin and MA026. The TJ opening activity of MA026 when binding to claudin-1 is a key to new avenues for transdermal administration of large hydrophilic biologics.
从 2002 年分离的 Pseudomonas sp. RtlB026 中提取的天然 14 元环内酰胺 MA026 的结构经 HPLC、MS/MS 和 NMR 的物理化学分析进行了修正，并通过全固相合成得到了证实。修正后的结构与之前报道的结构不同，其中两个氨基酸残基被错误地指定，现已被替换。合成的具有修正结构的 MA026 在基于细胞的 TJ 开放测定中显示出与天然 MA026 相似的紧密连接 (TJ) 开放活性。对 RtIB026 中推定的 MA026 生物合成基因簇 (BGC) 的生物信息学分析表明，修正结构中每个氨基酸残基的立体化学可以得到合理的解释。与黄杆菌素 BGC 的系统发育分析表明，黄杆菌素和 MA026 之间具有极高的同源性（约 90%）。当 MA026 与 Claudin-1 结合时，TJ 开放活性是经皮给予大亲水性生物制剂的新途径的关键。
