Centro Singular de Investigación en Química Biolóxica e, Materiais Moleculares (CIQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, Campus Vida, 15782, Santiago de Compostela, Spain.
Centro de Investigaciones Biológicas (CIB) del CSIC, C/Ramiro de Maetzu 9, CP, 28040, Madrid, Spain.
Chembiochem. 2019 Jun 3;20(11):1400-1409. doi: 10.1002/cbic.201800720. Epub 2019 Apr 12.
The cell membrane regulates the exchange of molecules and information with the external environment. However, this control barrier hinders the delivery of exogenous bioactive molecules that can be applied to correct cellular malfunctions. Therefore, the traffic of macromolecules across the cell membrane represents a great challenge for the development of the next generation of therapies and diagnostic methods. Cell-penetrating peptides are short peptide sequences capable of delivering a broad range of biomacromolecules across the cellular membrane. However, penetrating peptides still suffer from limitations, mainly related to their lack of specificity and potential toxicity. Glycosylation has emerged as a potential promising strategy for the biological improvement of synthetic materials. In this work we have developed a new convergent strategy for the synthesis of penetrating peptides functionalized with glycan residues by an oxime bond connection. The uptake efficiency and intracellular distribution of these glycopeptides have been systematically characterized by means of flow cytometry and confocal microscopy and in zebrafish animal models. The incorporation of these glycan residues into the peptide structure influenced the internalization efficiency and cellular toxicity of the resulting glycopeptide hybrids in the different cell lines tested. The results reported herein highlight the potential of the glycosylation of penetrating peptides to modulate their activity.
细胞膜调节与外部环境的分子和信息交换。然而，这种控制障碍阻碍了外源性生物活性分子的传递，这些分子可以应用于纠正细胞功能障碍。因此，大分子穿过细胞膜的运输对下一代治疗和诊断方法的发展构成了巨大挑战。细胞穿透肽是能够将广泛的生物大分子穿过细胞膜的短肽序列。然而，穿透肽仍然存在一些局限性，主要与其缺乏特异性和潜在毒性有关。糖基化已成为提高合成材料生物学性能的一种有前途的策略。在这项工作中，我们开发了一种新的汇聚策略，通过肟键连接，在穿透肽上功能化糖基残基。通过流式细胞术和共聚焦显微镜以及斑马鱼动物模型，系统地表征了这些糖肽的摄取效率和细胞内分布。这些糖基残基的掺入到肽结构中影响了所得糖肽杂化物在不同测试细胞系中的内化效率和细胞毒性。本文报道的结果强调了糖基化穿透肽调节其活性的潜力。
