Wada Shun-ichi, Urase Tomoe, Hasegawa Yuka, Ban Kenta, Sudani Aya, Kawai Yui, Hayashi Junsuke, Urata Hidehito
Bioorg Med Chem. 2014 Dec 15;22(24):6776-80. doi: 10.1016/j.bmc.2014.10.040.
α-Aminoisobutyric acid (Aib)-containing peptide analogs derived from TV-XIIa, a cell-penetrating peptide (CPP), were synthesized to explore structure-activity relationships. The replacement of Aib at position 1, 5, or 9 in the TV-XIIa amino acid sequence with alanine (Ala) suppressed the cellular uptake,whereas the simultaneous substitution of the two proline (Pro) residues at positions 6 and 10 with Aib(P-IV) considerably increased the cellular uptake. In order to explore the potential use of the Aib-containing peptide analogs for the cellular delivery of oligonucleotides (ODNs), we synthesized a covalent conjugate (P-IV-AON) of a 15-mer antisense ODN, which is complementary to luciferase gene, with P-IV, and the antisense effect of the P-IV-AON conjugate on luciferase expression in A549 cells was examined. Luciferase expression was decreased in the presence of the conjugate upon treatment with the reaction buffer at the concentrations of 5 and 10 μM.
为了探究构效关系，合成了源自穿膜肽（CPP）TV-XIIa的含α-氨基异丁酸（Aib）的肽类似物。用丙氨酸（Ala）取代TV-XIIa氨基酸序列中第1、5或9位的Aib会抑制细胞摄取，而同时用Aib（P-IV）取代第6和10位的两个脯氨酸（Pro）残基则会显著增加细胞摄取。为了探究含Aib的肽类似物用于寡核苷酸（ODN）细胞递送的潜在用途，我们合成了与荧光素酶基因互补的15聚体反义ODN与P-IV的共价缀合物（P-IV-AON），并检测了P-IV-AON缀合物对A549细胞中荧光素酶表达的反义作用。在用反应缓冲液处理时，在5和10μM浓度下，缀合物存在时荧光素酶表达降低。
