Optimization of antimicrobial peptide Smp43 as novel inhibitors of Cancer

Smp43 is a natural antimicrobial peptide derived from scorpion venom containing 43 amino acids, which inhibits the proliferation of various cancer cells, providing a new surrogate for antitumor drug discovery. However, Smp43 is large (Mw: 4653 Da) and unstable as a linear peptide. We truncated Smp43 to identify the key fragment and found that Smp(1-14) displayed significant antitumor activity. Subsequent optimization of Smp(1-14) led to a series of stapled peptides, among which SSmp6 demonstrated enhanced antitumor activity, stability, and membrane permeability compared to the linear peptides. Moreover, SSmp6 could decrease the phosphorylation of AKT, damage cancer cell membranes, and induce cell apoptosis. The results highlight the potential of SSmp6 as a lead stapled peptide for developing novel antitumor therapies. The study introduces a concept for using antimicrobial peptides to develop anticancer drugs.