Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering , Tokyo Medical and Dental University (TMDU) , 2-3-10 Kandasurugadai , Chiyoda-ku, Tokyo 101-0062 , Japan.
Bioconjug Chem. 2018 Jun 20;29(6):2050-2057. doi: 10.1021/acs.bioconjchem.8b00250. Epub 2018 May 31.
A cyclic decapeptide, CQTPYYMNTC (1), which mimics the dimerization arm of the EGF receptor (EGFR), was previously found to be captured into cells. We have sought to investigate the promising potential of this peptide as an intracellular delivery vehicle directed to EGFR-positive cells. The selectivity of peptide 1 to the EGFR was confirmed by a positive correlation between the expression level of the receptor and the cellular uptake of peptide 1 as shown by siRNA knockdown of the EGFR. The proapoptotic domain (PAD) peptide ([KLAKLAK]) has limited use due to a deficiency of cell membrane permeability resulting from cationic sequences and lack of specificity for cancer cells. As a proof-of-concept study, the cellular delivery of the PAD peptide was challenged by conjugation with peptide 1. The cellular uptake of a conjugated peptide 2, which was composed of peptide 1, the PAD peptide, and a linker cleavable with a protease, was evaluated by treatment of an EGFR-positive lung carcinoma cell line, A549. Significant suppression of proliferation by peptide 2 was shown in the results of a cell viability assay. The PAD peptide alone had no effect on the cells. The results suggest that peptide 1 is a promising lead compound as a new intracellular delivery vehicle for therapeutically effective peptides.
一种环状十肽，CQTPYYMNTC（1），模拟了表皮生长因子受体（EGFR）的二聚化臂，之前被发现可以被细胞摄取。我们一直在探索这种肽作为一种针对 EGFR 阳性细胞的细胞内递药载体的潜在应用。通过 EGFR 的 siRNA 敲低，显示了肽 1 对 EGFR 的选择性与受体表达水平和肽 1 的细胞摄取之间呈正相关。由于阳离子序列导致细胞膜通透性不足以及缺乏对癌细胞的特异性，促凋亡结构域（PAD）肽（[KLAKLAK]）的应用受到限制。作为概念验证研究，通过与肽 1 缀合来挑战 PAD 肽的细胞递送。通过用蛋白酶可切割的接头将组成肽 1、PAD 肽和接头的缀合肽 2 处理 EGFR 阳性肺癌细胞系 A549，评估其细胞摄取。细胞活力测定结果表明，肽 2 对细胞增殖有显著抑制作用。单独的 PAD 肽对细胞没有影响。这些结果表明，肽 1 是一种很有前途的先导化合物，可作为治疗有效肽的新型细胞内递药载体。
