Hu Xiao, He Yanhua, Wu Liping, Hao Yujun, Wang Zhenghe, Zheng Weiping
School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China.
Department of Genetics & Genome Sciences and Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Bioorg Med Chem Lett. 2017 Dec 15;27(24):5446-5449. doi: 10.1016/j.bmcl.2017.10.076. Epub 2017 Nov 12.
To follow up on our recent discovery of the 18-amino acid all-hydrocarbon [i, i + 4]-stapled p110α[E545K] peptide 1 that was shown to potently block the intracellular p110α[E545K]-IRS1 interaction (a protein-protein interaction uniquely present in cancer cells expressing p110α[E545K]) and the growth of the xenograft tumors formed by cancers harboring this mutation, in the current study we prepared and examined six derivatives of 1, i.e. stapled peptides 2-A, 2-B, 3-A, 3-B, 4-A, 4-B. We found that 2-A, 2-B, 4-A, and 4-B had higher % α-helicity than 1; moreover, the enhanced % α-helicity also led to an enhanced proteolytic stability. When compared with 1, the structurally simplified 14-amino acid 4-A and 4-B were found to more potently deactivate the AKT phosphorylation at Ser473 in the p110α[E545K]-expressing colon cancer cells, whose activation was previously demonstrated by us to be specifically derived from the p110α[E545K]-IRS1 interaction. The preliminary findings from the current study have laid a foundation for future more extensive studies on the stapled p110α[E545K] peptides newly identified in the current study.
为跟进我们最近发现的18个氨基酸的全烃类[i, i + 4] - 订书钉修饰的p110α[E545K]肽1，该肽已被证明能有效阻断细胞内p110α[E545K] - IRS1相互作用（一种仅在表达p110α[E545K]的癌细胞中存在的蛋白质 - 蛋白质相互作用）以及由携带该突变的癌症形成的异种移植肿瘤的生长，在本研究中，我们制备并检测了1的六种衍生物，即订书钉修饰的肽2 - A、2 - B、3 - A、3 - B、4 - A、4 - B。我们发现2 - A、2 - B、4 - A和4 - B的α - 螺旋百分比高于1；此外，α - 螺旋百分比的提高也导致了蛋白水解稳定性的增强。与1相比，结构简化的14个氨基酸的4 - A和4 - B在表达p110α[E545K]的结肠癌细胞中能更有效地使Ser473位点的AKT磷酸化失活，我们之前已证明该位点的激活特异性源自p110α[E545K] - IRS1相互作用。本研究的初步发现为未来对本研究中新鉴定的订书钉修饰的p110α[E545K]肽进行更广泛的研究奠定了基础。
