Activatable anticancer peptides with mutually suppressed bioactivity and their induced cytotoxicity by matrix metalloproteinase-2†

Using activatable cell penetrating peptides (CPPs) are one of the most important strategies to overcome the low selectivity of CPPs by controlling the activity of positively charged CPPs through conjugation with a negatively charged sequence via an enzyme-mediated cleavable linker. In this study, anionic antimicrobial peptides are utilized as the negatively charged component of these activatable CPPs to gain an additional bioactive function such as selective anticancer therapy after activation by enzymatic cleavage. Without an enzyme, the bioactivities of both anionic and cationic components are mutually suppressed by electrostatic interaction within the intact peptide structure. After enzymatic cleavage, the electrostatic interactions between the negative and positive peptide fragments are disrupted, restoring the individual peptide bioactivities and leading to synergistic anticancer therapeutic efficacy.