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引用次数: 0
摘要
涉及短 α - 螺旋片段的蛋白质-蛋白质相互作用(PPIs)在细胞过程中至关重要。对 α -螺旋肽进行钉合可提高它们的构象稳定性、亲和力和对蛋白酶的抵抗力。ELMO蛋白(ELMO1和ELMO2)在细胞过程中起着至关重要的作用,最近的研究强调了ELMO1在与DOCK2相互作用和调节DOCK2水平方面的独特作用。为了充分发挥模仿 DOCK 蛋白的多肽干扰 ELMO/DOCK 相互作用的治疗潜力,我们建议使用脱氧胆酸和传统小分子进行钉合,从而提高这些多肽的治疗潜力。我们的方法采用固相多肽合成技术,策略性地加入两个半胱氨酸氨基酸,在订书机中形成定义明确的受约束环肽。除了结构稳定外,这些钉合肽还具有显著的蛋白水解稳定性,即使在人体血清存在的情况下也不会被酶降解。
Synthesis and Optimization of Stapled DOCK Peptides
with Improved Drug-like Properties
Protein-protein interactions (PPIs) involving short α -helix fragments are of critical importance in cellular processes. Stapling of α -helical peptides improves their conformational stability, affinity, and resistance to proteases. ELMO proteins (ELMO1 and ELMO2) play a crucial role in cellular processes, and recent studies highlight ELMO1's distinct role in interacting with, and modulating, DOCK2 levels. To harness the full therapeutic potential of peptides mimicking the DOCK protein for interference with the ELMO/DOCK interaction, we propose employing deoxycholic acid and conventional small molecules for stapling, thus enhancing the therapeutic potential of these peptides. Our method employs solid-phase peptide synthesis, strategically incorporating two cysteine amino acids to create well-defined, constrained cyclic peptides upon stapling. In addition to their structural stabilisation, these stapled peptides exhibit remarkable proteolytic stability, defying enzymatic degradation, even in the presence of human serum.
期刊介绍:
Arkivoc publishes full papers (not accounts) describing sound original work that is of interest to organic chemists (in areas of synthetic organic chemistry, bio-organic, organometallic, theoretical, and physical organic chemistry:
General Papers describing sound original work
Reviews and Accounts of selected topics
Honorary Issues - Pay tribute to distinguished organic chemists (invited contributions)
Thematic Issues - Cover important current topics in organic chemistry
Regional Issues - Recognize organic chemistry in various countries.