Arginine modification of lycosin-I to improve inhibitory activity against cancer cells

Abstract

Lycosin-I is a linear amphipathic α-helical anticancer peptide (ACP) extracted from the spider Lycosa singoriensis, which can activate the mitochondrial death pathway to induce apoptosis in tumor cells and up-regulate p27 to inhibit cell proliferation. However, the applicability of lycosin-I as a novel anticancer drug is limited by its low cellular entry and efficacy in solid tumors. Amino acid substitution presents an effective and modest strategy to improve the anticancer activity and bioavailability of ACPs. Herein, an arginine-modified lycosin-I (named R-lycosin-I) was designed and synthesized by substituting lysine (Lys) with arginine (Arg). This peptide exhibited higher anticancer activity and penetrability against solid tumor cells than lycosin-I. They displayed noticeable differences in their physicochemical properties including the secondary structure, hydrodynamic size, and zeta potential. Fluorescence analyses have confirmed that R-lycosin-I exhibits increased cellular uptake and improved intracellular distribution. Due to its superior physical and chemical properties and high serum stability, R-lycosin-I could penetrate deeply into tumor spheroids and produce strong toxicity in the 3D tumor model. Overall, these findings suggest that arginine modification may provide an effective strategy for improving the anticancer activity of lycosin-I, and R-lycosin-I may be a useful lead for developing anticancer drugs.

Spider venom peptides as potential drug candidates due to their anticancer and antinociceptive activities

“…To enhance the cellular entry and efficacy in solid tumor, the method of substituting one amino acid (from Lys to Arg) was utilized to design a synthetic cationic peptide (Lycosin- I to R- Lycosin-I). Compared with lycosin-I, R-lycosin-I demonstrated higher inhibitory activity and selectivity toward cancer cells [37]. Based on its characteristics mentioned above, lycosin- I is recognized as a cell-penetrating peptide that can be used for the intracellular delivery of functional materials to circumvent the biomembrane barrier by conjugating with spherical gold nanoparticles.…”

“…Based on its characteristics mentioned above, lycosin- I is recognized as a cell-penetrating peptide that can be used for the intracellular delivery of functional materials to circumvent the biomembrane barrier by conjugating with spherical gold nanoparticles. This conjunction will provide a stable, efficient and higher selective platform to diagnose and treat cancers correctly in the future [6, 37].…”

Anti-metastatic Effects of Cationic KT2 Peptide (a Lysine/Tryptophan-rich Peptide) on Human Melanoma A375.S2 Cells

“…A large number of bioactive peptides contain specific kinds of amino acids and can be referred to as tryptophan-, proline-, cysteine-, arginine-, or lysine-rich (14,15). These compositions affect cell membrane interactions, cell penetration, and cell-selective, antibacterial or anticancer activities (15)(16)(17)(18). Some bioactive peptides, such as leucine/lysine-rich K6L9 peptide (19), CT20p peptide (20), and 9R-P201 peptide (21), have anti-metastatic effects.…”

Versatile spider venom peptides and their medical and agricultural applications

“…However, due to its somewhat limited penetration ability with regard to solid tumors, recent research has involved increasing selectivity for tumor cells and improving internalization efficiency of the peptide. A simple substitution of the seven lysines in Lycosin-I to arginine increased the stability, membrane binding and cell penetration (by improving cellular uptake and endocytic release intracellularly) into cancer cells in an ex vivo model of human tumors (Zhang et al, 2017).…”

“…Lycosin-I is an extremely promising candidate for anti-cancer therapeutic development both to induce apoptosis of cancer cells and reduce likelihood of further metastases. The arginine-substituted form of the peptide has the more desirable properties in terms of stability, size and penetrability (Zhang et al, 2017) and its ability to be chemically synthesized makes it highly suitable for further preclinical development. Several more recent activities and potential therapeutic applications for the peptide have also been discovered and Fernandez-Rojo, 2018).…”