Department of Biology, Research Institute of Life Science, Gyeongsang National University, 900 Gajwa-dong, Jinju 660-701, Republic of Korea.
Peptides. 2011 May;32(5):895-9. doi: 10.1016/j.peptides.2011.02.010. Epub 2011 Feb 18.
Buforin IIb is a novel cell-penetrating anticancer peptide derived from histone H2A. In this study, we enhanced the cancer targeting specificity of buforin IIb using a tumor-associated enzyme-controlled activation strategy. Buforin IIb was fused with an anionic peptide (modified magainin intervening sequence, MMIS), which neutralizes the positive charge of buforin IIb and thus renders it inactive, via a matrix metalloproteinases (MMPs)-cleavable linker. The resulting MMIS:buforin IIb fusion peptide was completely inactive against MMPs-nonproducing cells. However, when the fusion peptide was administrated to MMPs-producing cancer cells, it regained the killing activity by releasing free buforin IIb through MMPs-mediated cleavage. Moreover, the activity of the fusion peptide toward MMPs-producing cancer cells was significantly decreased when the cells were pretreated with a MMP inhibitor. Taken together, these data indicate that the cancer targeting specificity of MMIS:buforin IIb is enhanced compared to the parent peptide by reactivation at the specialized areas where MMPs are pathologically produced.
Buforin IIb 是一种新型的细胞穿透性抗癌肽，来源于组蛋白 H2A。在这项研究中，我们使用与肿瘤相关的酶控制激活策略来增强 Buforin IIb 的癌症靶向特异性。Buforin IIb 通过基质金属蛋白酶（MMPs）可切割的接头与阴离子肽（修饰的 Magainin 间隔序列，MMIS）融合，MMIS 中和了 Buforin IIb 的正电荷，从而使其失活。所得的 MMIS:buforin IIb 融合肽对 MMPs 非产生细胞完全没有活性。然而，当将融合肽施用于 MMPs 产生的癌细胞时，通过 MMPs 介导的切割释放游离的 Buforin IIb，融合肽恢复了杀伤活性。此外，当用 MMP 抑制剂预处理细胞时，融合肽对 MMPs 产生的癌细胞的活性显著降低。综上所述，这些数据表明，与母体肽相比，MMIS:buforin IIb 的癌症靶向特异性通过在 MMP 病理性产生的特定区域的再激活得到增强。
