Jbara Muhammad, Eid Emad, Brik Ashraf
Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa 3200008, Israel.
J Am Chem Soc. 2020 May 6;142(18):8203-8210. doi: 10.1021/jacs.9b13216. Epub 2020 Apr 27.
Chemists have been interested in the N-alkylation of a peptide bond because such a modification alters the conformation of the amide bond, interferes with hydrogen bond formation, and changes other properties of the peptide (e.g., solubility). This modification also opens the door for attaching functional groups for various applications. Nonetheless, the irreversibility of some of these modifications and the harsh conditions required for their removal currently limits the wide utility of this approach. Herein, we report applying a propargyl group for peptide bond modification at diverse junctions, which can be removed under mild and aqueous conditions via treatment with gold(I). Considering the straightforward conditions for both the installation and removal of this group, the propargyl group provides access to the benefits of backbone N-alkylation, while preserving the ability for on-demand depropargylation and full recovery of the native amide bond. This reversible modification was found to improve solid-phase peptide synthesis as demonstrated in the chemical synthesis of NEDD8 protein, without the use of special dipeptide analogues. Also, the reported approach was found to be useful in decaging a broad range of propargyl-based protecting groups used in chemical protein synthesis. Remarkably, reversing the order of the two residues in the propargylation site resulted in rapid amide bond cleavage, which extends the applicability of this approach beyond a removable backbone modification to a cleavable linker. The easy attach/detach of this functionality was also examined in loading and releasing of biotinylated peptides from streptavidin beads.
化学家们一直对肽键的N-烷基化感兴趣,因为这种修饰会改变酰胺键的构象,干扰氢键的形成,并改变肽的其他性质(如溶解度)。这种修饰还为连接各种应用的官能团打开了大门。然而,其中一些修饰的不可逆性以及去除它们所需的苛刻条件目前限制了这种方法的广泛应用。在此,我们报道了在不同连接点应用炔丙基进行肽键修饰,通过用一价金处理,可以在温和的水性条件下去除该修饰。考虑到该基团安装和去除的条件简单,炔丙基在保留按需脱炔丙基化和完全恢复天然酰胺键能力的同时,提供了主链N-烷基化的益处。这种可逆修饰被发现可改善固相肽合成,如在NEDD8蛋白的化学合成中所证明的,无需使用特殊的二肽类似物。此外,已发现所报道的方法在去除化学蛋白质合成中使用的多种基于炔丙基的保护基团方面很有用。值得注意的是,在炔丙基化位点反转两个残基的顺序会导致酰胺键快速裂解,这将该方法的适用性从可去除的主链修饰扩展到可裂解的连接子。还在从链霉亲和素珠上加载和释放生物素化肽的过程中研究了这种功能的轻松连接/分离。