化学
肽
环肽
细胞通透性
组合化学
膜透性
生物物理学
膜
小分子
生物化学
代谢稳定性
计算生物学
体外
生物
作者
Christian R. O. Bartling,Flora Alexopoulou,Sarah Kuschert,Yanni K.‐Y. Chin,Xinying Jia,Vita Sereikaitė,Dennis Özcelik,Torben Pilegaard Jensen,Palash Jain,Mads Nygaard,Kasper Harpsøe,David E. Gloriam,Mehdi Mobli,Kristian Strømgaard
标识
DOI:10.1021/acs.jmedchem.2c02017
摘要
Peptides targeting disease-relevant protein–protein interactions are an attractive class of therapeutics covering the otherwise undruggable space between small molecules and therapeutic proteins. However, peptides generally suffer from poor metabolic stability and low membrane permeability. Hence, peptide cyclization has become a valuable approach to develop linear peptide motifs into metabolically stable and potentially cell-permeable cyclic leads. Furthermore, cyclization of side chains, also known as “stapling”, can stabilize particular secondary peptide structures. Here, we demonstrate that a comprehensive examination of cyclization strategies in terms of position, chemistry, and length is a prerequisite for the selection of optimal cyclic peptide scaffolds. Our systematic approach identifies cyclic APP dodecamer peptides targeting the phosphotyrosine binding domain of Mint2 with substantially improved affinity. We show that especially all-hydrocarbon stapling provides improved metabolic stability, a significantly stabilized secondary structure and membrane permeability.
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