Department of Chemistry, Texas A & M University, Box 30012, College Station, Texas 77842, United States.
ZentriForce Pharma Research GmbH, Carl-Friedrich-Gauss-Ring 5, 69124 Heidelberg, Germany.
J Am Chem Soc. 2024 Apr 17;146(15):10331-10341. doi: 10.1021/jacs.3c11717. Epub 2024 Apr 4.
Disruption of protein-protein interactions is medicinally important. Interface helices may be mimicked in helical probes featuring enhanced rigidities, binding to protein targets, stabilities in serum, and cell uptake. This form of mimicry is dominated by stapling between side chains of helical residues: there has been less progress on helical -caps, and there were no generalizable -caps. Conversely, in natural proteins, helicities are stabilized and terminated by - and caps but not staples. Bicyclic caps previously introduced by us enable interface helical mimicry featuring rigid synthetic caps at both termini in this work. An unambiguously helical dual-capped system proved to be conformationally stable, binding cyclins A and E, and showed impressive cellular uptake. In addition, the dual-capped mimic was completely resistant to proteolysis in serum over an extended period when compared with "gold standard" hydrocarbon-stapled controls. Dual-capped peptidomimetics are a new, generalizable paradigm for helical interface probe design.
蛋白质-蛋白质相互作用的破坏在医学上很重要。具有增强刚性的螺旋探针可以模拟界面螺旋，从而与蛋白质靶标结合，在血清和细胞内具有稳定性。这种模拟形式主要由螺旋残基侧链之间的订书钉连接主导：在螺旋帽方面进展较少，也没有可推广的帽。相反，在天然蛋白质中，螺旋结构通过 - 和帽而不是订书钉来稳定和终止。我们之前引入的双环帽在这项工作中使两端都具有刚性合成帽的界面螺旋模拟成为可能。一个明确的双帽系统被证明是构象稳定的，能够结合细胞周期蛋白 A 和 E，并且表现出令人印象深刻的细胞摄取能力。此外，与“金标准”碳氢化合物订书钉对照相比，双帽模拟物在延长的血清中完全抵抗蛋白水解。双帽肽模拟物是一种新的、可推广的螺旋界面探针设计范例。
