Lee DaeYong, Noh Ilkoo, Yoo Jisang, Rejinold N Sanoj, Kim Yeu-Chun
Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
Acta Biomater. 2017 Jul 15;57:187-196. doi: 10.1016/j.actbio.2017.05.040. Epub 2017 May 17.
Helical peptides were naturally-occurring ordered conformations that mediated various biological functions essential for biotechnology. However, it was difficult for natural helical polypeptides to be applied in biomedical fields due to low bioavailability. To avoid these problems, synthetic alpha-helical polypeptides have recently been introduced by further modifying pendants in the side chain. In spite of an attractive biomimetic helical motif, these systems could not be tailored for targeted delivery mainly due to nonspecific binding events. To address these issues, we created a conformation-transformable polypeptide capable of eliciting a pH-activated cell-penetrating property solely at the cancer region. The developed novel polypeptide showed that the bare helical conformation had a function at physiological conditions while the pH-induced helical motif provided an active cell-penetrating characteristic at a tumor extracellular matrix pH. The unusual conformation-transformable system can elicit bioactive properties exclusively at mild acidic pH.
We developed pH-controllable cell-penetrating polypeptides (PCCPs) undergoing pH-induced conformational transitions. Unlike natural cell-penetrating peptides, PCCPs was capable of penetrating the plasma membranes dominantly at tumor pH, driven by pH-controlled helicity. The conformation of PCCPs at neutral pH showed low helical propensity because of dominant electrostatic attractions within the side chains. However, the helicity of PCCPs was considerably augmented by the balance of electrostatic interactions, thereby inducing selective cellular penetration. Three polypeptides undergoing different conformational transitions were prepared to verify the selective cellular uptake influenced by their structures. The PCCP undergoing low-to-high helical conformation provided the tumor specificity and enhanced uptake efficiency. pH-induced conformation-transformable polypeptide might provide a novel platform for stimuli-triggered targeting systems.
螺旋肽是介导生物技术所需各种生物学功能的天然有序构象。然而，由于生物利用度低，天然螺旋多肽难以应用于生物医学领域。为避免这些问题，最近通过进一步修饰侧链上的侧基引入了合成α-螺旋多肽。尽管具有吸引人的仿生螺旋基序，但这些系统主要由于非特异性结合事件而无法用于靶向递送。为解决这些问题，我们创建了一种构象可转变的多肽，其仅在癌症区域引发pH激活的细胞穿透特性。所开发的新型多肽表明，裸露的螺旋构象在生理条件下起作用，而pH诱导的螺旋基序在肿瘤细胞外基质pH下提供了活性细胞穿透特性。这种不寻常的构象可转变系统仅在轻度酸性pH下引发生物活性特性。
我们开发了经历pH诱导构象转变的pH可控细胞穿透多肽（PCCP）。与天然细胞穿透肽不同，PCCP能够在肿瘤pH下主要通过pH控制的螺旋度驱动穿透质膜。PCCP在中性pH下的构象由于侧链内主要的静电吸引力而显示出低螺旋倾向。然而，PCCP的螺旋度通过静电相互作用的平衡而显著增加，从而诱导选择性细胞穿透。制备了三种经历不同构象转变的多肽，以验证其结构对选择性细胞摄取的影响。经历低到高螺旋构象的PCCP提供了肿瘤特异性并提高了摄取效率。pH诱导的构象可转变多肽可能为刺激触发的靶向系统提供一个新平台。
