阻断Ras和Sevenless家族调节蛋白1（SOS1）之间的相互作用已成为治疗携带致癌性Ras突变的癌症的有吸引力的治疗策略。K-Ras突变是Ras驱动性癌症中最常见的，占86％，而N-Ras突变和H-Ras突变分别占11％和3％。在这里，我们报告了一系列烃稳定肽的设计和合成，以模拟SOS1的α-螺旋作为泛Ras抑制剂。在这些烃稳定肽中，SSOSH-5被确定为维持良好约束的α-螺旋结构并具有高亲和力与H-Ras结合。此外，通过结构建模分析，SSOSH-5还得到了与父线性肽相似的与Ras结合的验证。证明了这种优化的烃稳定肽能够通过调节下游激酶信号传导，在剂量依赖方式下有效抑制泛Ras突变癌细胞的增殖并诱导细胞凋亡。值得注意的是，SSOSH-5表现出高透过细胞膜和强大的蛋白水解抵抗力。我们证明了肽稳定策略是开发基于肽的泛Ras抑制剂的可行方法。此外，我们预计SSOSH-5可以进一步被表征和优化，以治疗Ras驱动的癌症。 版权所有 © 2023。Elsevier Inc. 发布。

Blocking the interaction between Ras and Son of Sevenless homolog 1 (SOS1) has been an attractive therapeutic strategy for treating cancers involving oncogenic Ras mutations. K-Ras mutation is the most common in Ras-driven cancers, accounting for 86%, with N-Ras mutation and H-Ras mutation accounting for 11% and 3%, respectively. Here, we report the design and synthesis of a series of hydrocarbon-stapled peptides to mimic the alpha-helix of SOS1 as pan-Ras inhibitors. Among these stapled peptides, SSOSH-5 was identified to maintain a well-constrained alpha-helical structure and bind to H-Ras with high affinity. SSOSH-5 was furthermore validated to bind with Ras similarly to the parent linear peptide through structural modeling analysis. This optimized stapled peptide was proven to be capable of effectively inhibiting the proliferation of pan-Ras-mutated cancer cells and inducing apoptosis in a dose-dependent manner by modulating downstream kinase signaling. Of note, SSOSH-5 exhibited a high capability of crossing cell membranes and strong proteolytic resistance. We demonstrated that the peptide stapling strategy is a feasible approach for developing peptide-based pan-Ras inhibitors. Furthermore, we expect that SSOSH-5 can be further characterized and optimized for the treatment of Ras-driven cancers.Copyright © 2023. Published by Elsevier Inc.