Abstract
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.
The design and synthesis of a heptapeptide (1; see scheme) based on the structure of galactin‐3, which can self‐assemble into nanofibers, has been reported. Although the proteolysis of the peptides leads to a moderate cytotoxicity of the molecule on cancer cells, co‐incubation of a proteasome inhibitor BTZ with the peptide significantly decreases the proteolysis of the peptide and enhances the activity of the peptide nanofibers for inhibiting the cancer cells.