The stimuli-responsive conformational transformation of peptides possessing a constrained form triggered by specific biological microenvironment would provide an effective strategy for the development of highly specific peptide therapeutics. Here, we developed a peptide containing a cytotoxic helical KLA sequence with therapeutic specificity through the use of stimuli-responsive conformational transformation. The KLA peptide is modified to form a cyclic structure to allow for constrained helicity that confers low cytotoxicity. The modified KLA peptide is electrostatically complexed to hyaluronic acid to facilitate enhanced endocytosis into the cancer cells. After endocytosis, the peptide is released from the complex into the cellular cytoplasm by hyaluronidases on the surface of the cellular membrane. Specific intracellular stimuli then trigger the release of the strain that suppresses peptide helicity, and the inherent helical conformation of the KLA peptide is restored. Therefore, the stimuli-responsive conformational transformation of a peptide from low to high helicity selectively induces cell death by disruption of the plasma and mitochondrial membrane.

中文翻译：

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肽对细胞毒性的刺激反应性构象转化。

具有由特定的生物微环境触发的受限形式的肽的刺激响应构象转化将为开发高度特异性的肽治疗剂提供有效的策略。在这里，我们通过使用刺激响应构象转化开发了一种具有治疗特异性的细胞毒性螺旋KLA序列的肽。修饰KLA肽以形成环状结构，以使其具有限制的螺旋度，从而赋予较低的细胞毒性。修饰的KLA肽与透明质酸静电复合，以促进增强的向癌细胞内吞。内吞后，通过透明质酸酶在细胞膜表面将肽从复合物中释放到细胞质中。然后，特定的细胞内刺激触发释放抑制肽螺旋的菌株，并恢复了KLA肽固有的螺旋构象。因此，肽从低螺旋性到高螺旋性的刺激响应构象转化通过破坏血浆和线粒体膜而选择性地诱导细胞死亡。