Tarchoun Karima, Soltész Dóra, Farkas Viktor, Lee Ho-Jin, Szabó Ildikó, Bánóczi Zoltán
Institute of Chemistry, Faculty of Science, ELTE Eötvös Loránd University, Pázmány Péter sétány 1/A, 1117 Budapest, Hungary.
Hevesy György PhD School of Chemistry, Institute of Chemistry, ELTE Eötvös Loránd University, Pázmány Péter sétány 1/A, 1117 Budapest, Hungary.
Pharmaceutics. 2024 Mar 30;16(4):477. doi: 10.3390/pharmaceutics16040477.
The cell-penetrating peptide (CPP) penetratin has gained much attention over many years due to its potential role as a transporter for a broad range of cargo into cells. The modification of penetratin has been extensively investigated too. Aza-peptides are peptide analogs in which one or more of the amino residues are replaced by a semicarbazide. This substitution results in conformational restrictions and modifications in hydrogen bonding properties, which affect the structure and may lead to enhanced activity and selectivity of the modified peptide. In this work, the Trp residues of penetratin were substituted by aza-glycine or glycine residues to examine the effect of these modifications on the cellular uptake and the internalization mechanism. The substitution of Trp or Trp dramatically reduced the internalization, showing the importance of Trp in cellular uptake. Interestingly, while aza-glycine in the position of Trp increased the cellular uptake, Gly reduced it. The two Trp-modified derivatives showed altered internalization pathways, too. Based on our knowledge, this is the first study about the effect of aza-amino acid substitution on the cell entry of CPPs. Our results suggest that aza-amino acid insertion is a useful modification to change the internalization of a CPP.
多年来，细胞穿透肽（CPP）穿膜肽因其作为多种货物进入细胞的转运体的潜在作用而备受关注。对穿膜肽的修饰也进行了广泛研究。氮杂肽是一种肽类似物，其中一个或多个氨基残基被氨基脲取代。这种取代导致构象限制和氢键性质的改变，从而影响结构，并可能导致修饰后肽的活性和选择性增强。在这项工作中，将穿膜肽的色氨酸残基用氮杂甘氨酸或甘氨酸残基取代，以研究这些修饰对细胞摄取和内化机制的影响。色氨酸或色氨酸的取代显著降低了内化作用，表明色氨酸在细胞摄取中的重要性。有趣的是，虽然色氨酸位置的氮杂甘氨酸增加了细胞摄取，但甘氨酸却降低了细胞摄取。两种色氨酸修饰的衍生物也显示出内化途径的改变。据我们所知，这是第一项关于氮杂氨基酸取代对CPPs细胞内吞作用影响的研究。我们的结果表明，插入氮杂氨基酸是改变CPP内化作用的一种有用修饰。
