We report the reversible transformation between a singly stapled dynamic α‐helical peptide and a doubly stapled quasi‐static one through redox‐triggered dithiol/disulfide conversions of a stapling moiety. This process allows the rate of interconversion between the right‐handed (P) and left‐handed (M) α‐helices to be altered by a factor of approximately 103 before and after the transformation. An as‐obtained doubly stapled α‐helical peptide, which is composed of an achiral peptide having an L‐valine carboxylic acid residue at the C‐terminus, a disulfide‐based reversible staple, and a biphenyl‐based fixed staple, adopts an (M)‐rich form as a kinetically trapped state. The (M)‐rich helix was subsequently transformed into the thermodynamically stable (P)‐rich form in 1,1,2,2‐tetrachloroethane with the half‐life time (t1/2) of approximately 44 days at 25 ºC. Reduction of the doubly stapled peptide with tri‐n‐butylphosphine in tetrahydrofuran/water (10/1, v/v) produced the corresponding singly stapled dynamic α‐helical peptide bearing two thiol groups at the side chains, which underwent solvent‐induced reversible helicity inversion. The resulting dithiol of the singly stapled peptide could be reoxidized to form the original doubly stapled form using 4,4’‐dithiodipyridine. Furthermore, the P/M interconversion of a doubly stapled peptide with two flexible hydrocarbon‐based staples is considerably more rapid than that with more rigid staples.

中文翻译：

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氧化还原触发动态和准静态α螺旋肽之间的可逆转换


我们报告了通过氧化还原触发的装订部分的二硫醇/二硫化物转化，单钉动态α螺旋肽和双钉准静态肽之间的可逆转变。这个过程使得右旋 (P) 和左旋 (M) α 螺旋之间的相互转化率在转化前后改变约 103 倍。所获得的双钉合α螺旋肽由C端具有L-缬氨酸残基的非手性肽、基于二硫键的可逆钉和基于联苯的固定钉组成，采用( M) 富集形式作为动力学捕获态。随后，富含 (M) 的螺旋在 1,1,2,2-四氯乙烷中转化为热力学稳定的富含 (P) 形式，25 ℃ 下的半衰期 (t1/2) 约为 44 天。在四氢呋喃/水（10/1，v/v）中用三正丁基膦还原双钉肽，产生相应的单钉动态 α 螺旋肽，在侧链上带有两个硫醇基团，该肽经历了溶剂诱导的可逆性螺旋性反转。使用 4,4'-二硫代二吡啶可以将所得的单钉肽的二硫醇重新氧化形成原始的双钉形式。此外，双钉肽与两个柔性烃基钉的 P/M 互变比使用更刚性的钉的 P/M 互变要快得多。