Department of Chemistry, Brandeis University, 415 South St, Waltham, MA, 02454, USA.
Chem Asian J. 2018 Nov 16;13(22):3464-3468. doi: 10.1002/asia.201800875. Epub 2018 Jul 24.
Nanofibers of short peptides are emerging as a promising type of agents for inhibiting cancer cells. But the proteolysis of peptides decreases the anticancer efficacy of the peptide nanofibers. Here we show that decreasing the activity of proteasomes enhance the activity of peptide nanofibers for inhibiting cancer cells. Based on the structure of galactin-3, we designed a heptapeptide, which self-assembles to form nanofibers. The nanofibers of the heptapeptide exhibit moderate cytotoxicity to three representative cancer cell lines (HeLa, MCF-7, and HepG2), largely due to the proteolysis of the peptides. Using a clinically approved proteasome inhibitor, bortezomib, to treat the cancer cells significantly decreases the proteolysis of the peptides and enhances the activity of the peptide nanofibers for inhibiting the cancer cells. This work illustrates a promising approach for enhancing the anticancer efficacy of peptide nanofibers by modulating intracellular protein degradation machinery, as well as provides insights for understanding the cytotoxicity of aberrant protein or peptide aggregates in complicated cellular environment.
短肽纳米纤维作为一种有前途的抑制癌细胞的药物正在兴起。但是肽的蛋白水解会降低肽纳米纤维的抗癌效果。在这里，我们表明降低蛋白酶体的活性可以增强肽纳米纤维抑制癌细胞的活性。基于半乳糖凝集素-3 的结构，我们设计了一种七肽，它可以自组装形成纳米纤维。该七肽的纳米纤维对三种代表性的癌细胞系（HeLa、MCF-7 和 HepG2）表现出中等的细胞毒性，主要是由于肽的蛋白水解。使用临床批准的蛋白酶体抑制剂硼替佐米治疗癌细胞，可显著降低肽的蛋白水解，并增强肽纳米纤维抑制癌细胞的活性。这项工作说明了通过调节细胞内蛋白质降解机制来增强肽纳米纤维抗癌效果的一种很有前途的方法，并为理解复杂细胞环境中异常蛋白质或肽聚集体的细胞毒性提供了思路。
