State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China.
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, 90095, USA.
Angew Chem Int Ed Engl. 2021 Mar 15;60(12):6646-6652. doi: 10.1002/anie.202016267. Epub 2021 Feb 12.
Stapling of peptides by intramolecular crosslinking of two neighboring amino acid side chains offers an important tool to modulate the structure and properties of peptides. In comparison to the stapling of artificially engineered peptide substrates, methods for stapling native peptides are more desirable for easier accessibility and genetic encodability. However, the existing strategy for selectivity control in the stapling of native peptides is relatively limited: the site of anchoring is often dominated by Cys, and the means for achieving the position selectivity among the same type of residues at different locations is lacking. We have developed a simple and powerful strategy for stapling native peptides at lysine residues with formaldehyde by the cooperation of nearby tyrosine or arginine residues. The stapling reactions can proceed with high efficiency and residue selectivity under mild conditions, and generate linchpins with distinct physiochemical properties. The new method for peptide stapling enables unique control of position-selectivity for substrates bearing multiple reaction sites by reactivity that can be readily built in the peptide sequence.
通过两个相邻氨基酸侧链的分子内交联将肽钉合提供了调节肽结构和性质的重要工具。与人工工程化肽底物的钉合相比，用于天然肽的钉合的方法更可取，因为其更容易获得且具有遗传编码能力。然而，在天然肽的钉合中，选择性控制的现有策略相对有限：锚固位点通常由半胱氨酸主导，并且缺乏在不同位置的同种残基之间实现位置选择性的手段。我们通过附近的酪氨酸或精氨酸残基的合作，开发了一种在赖氨酸残基上用甲醛将天然肽钉合的简单而强大的策略。在温和的条件下，钉合反应可以以高效率和残基选择性进行，并生成具有独特物理化学性质的连接子。用于肽钉合的新方法通过可以在肽序列中轻松构建的反应性，为具有多个反应位点的底物提供了独特的位置选择性控制。
