Mehrani Mona, Lella Muralikrishna, Graham Katherine A, Borotto Nicholas B, Tal-Gan Yftah
Department of Chemistry, University of Nevada, Reno, 1664 North Virginia Street, Reno, NV 89557, USA.
Org Biomol Chem. 2025 Feb 5;23(6):1359-1372. doi: 10.1039/d4ob01524j.
Cyclization is a widely used approach to exert conformational restraint on linear peptide sequences. Herein, urea bridge chemistry was deployed to achieve side chain-to-side chain peptide cyclization on the CSP1-E1A peptide scaffold. To determine the effects of ring size and bridge position on the overall peptide conformation and find the ideal area within the CSP sequence for cyclization, we performed biological evaluation as well as secondary structure analysis on all the cyclic analogs. Biological evaluation results exhibited that even minor modifications to cyclic analogs for each of the cyclization positions could significantly alter the interaction between the peptide and its target receptor, ComD. Furthermore, structural analysis using circular dichroism (CD) and Trapped Ion Mobility Spectrometry (TIMS) emphasized the significance of incorporating the bridge position as a parameter to be modified, in addition to the traditional ring position and ring size parameters. Overall, our results showcase the importance of comprehensive conformational screening in fine-tuning the secondary structure of cyclic peptide analogs. This knowledge could be very useful for future studies aimed at optimizing peptide : protein interactions.
环化是一种广泛应用于对线性肽序列施加构象限制的方法。在此，利用脲桥化学在CSP1-E1A肽支架上实现侧链对侧链的肽环化。为了确定环大小和桥位置对整体肽构象的影响，并在CSP序列中找到理想的环化区域，我们对所有环状类似物进行了生物学评估以及二级结构分析。生物学评估结果表明，即使对每个环化位置的环状类似物进行微小修饰，也可能显著改变肽与其靶受体ComD之间的相互作用。此外，使用圆二色性（CD）和捕获离子淌度光谱（TIMS）进行的结构分析强调了除了传统的环位置和环大小参数外，将桥位置作为一个待修饰参数的重要性。总体而言，我们的结果表明了全面构象筛选在微调环状肽类似物二级结构中的重要性。这一知识对于未来旨在优化肽与蛋白质相互作用的研究可能非常有用。
