Cell-penetrating peptides (CPPs) have been widely utilized as efficient molecular tools for the delivery of bioactive cargoes such as peptides, proteins, and genetic material. However, to improve their versatility as tools in biological environments, the resistance of CPPs to enzymatic degradation and their structural stability must be improved to achieve long-term efficacy. Here we designed and synthesized novel artificial CPPs, poly(LysAibXaa), containing periodic α-aminoisobutyric acid (Aib) and l-lysine by chemoenzymatic polymerization. Poly(LysAibAla) tended to form 3₁₀- and α-helical structures under the amphiphilic cell-membrane-mimicking environment. Poly(LysAibXaa) exhibited long-term internalization and thus high accumulation in live cells, which is attributed to the improvement in the resistance to proteolytic digestion as a result of the incorporation of Aib residues into the peptide backbone. We presented a simple molecular design and synthesis of efficient CPPs applicable to both human and plant cells with long-term stability and negligible cytotoxicity.

中文翻译：

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含有周期性α-氨基异丁酸的人工穿透细胞肽，在人和植物细胞中具有长期内在化效率

细胞穿透肽（CPPs）已被广泛用作有效的分子工具，以输送生物活性货物，例如肽，蛋白质和遗传物质。但是，为了提高其在生物环境中作为工具的多功能性，必须提高CPP对酶促降解的抗性及其结构稳定性，以实现长期疗效。在这里，我们设计和合成了新型人工CPPs，聚（LysAibXaa），其中包含周期性的α-氨基异丁酸（Aib）和1-赖氨酸，通过化学酶促聚合反应合成。聚（LysAibAla）倾向于形成3 ₁₀两亲性细胞膜模拟环境下的α和α螺旋结构。聚（LysAibXaa）表现出长期内在化，因此在活细胞中具有很高的积累，这归因于由于将Aib残基掺入肽主链而提高了对蛋白水解消化的抵抗力。我们提出了一种简单的分子设计和有效CPP的合成，适用于具有长期稳定性和可忽略的细胞毒性的人和植物细胞。