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    Correlation between the secondary structure and surface activity of beta-sheet forming cationic amphiphilic peptides and their anticancer activity

    Year: 2022

    Journal: Colloid Surf. B-Biointerfaces, Volume 209, JAN

    Authors: Hadianamrei, Roja; Tomeh, Mhd Anas; Brown, Stephen; Wang, Jiqian; Zhao, Xiubo

    Organizations: EPSRC, UK [EP/N007174/1, EP/N023579/1]; Royal Society, UK [RG160662, IE150457]; Jiangsu specially appointed professor program, China; University of Sheffield; EPSRC [EP/N023579/1, EP/N007174/1] Funding Source: UKRI

    Keywords: Anticancer peptides; Cationic amphiphilic peptides; Beta sheet peptides; Cervical cancer; Colorectal cancer; Surface activity

    Cancer is one of the main causes of death worldwide. The current cancer treatment strategies often lack selectivity for cancer cells resulting in dose-limiting adverse effects and reduced quality of life. Recently, anticancer peptides (ACPs) have emerged as an alternative treatment with higher selectivity, less adverse effects, and lower propensity for drug resistance. However, most of the current studies on the ACPs are focused on alpha-helical ACPs and there is lack of systematic studies on beta-sheet forming ACPs. Herein we report the development of a new series of rationally designed short cationic amphiphilic beta-sheet forming ACPs and their structure activity relationship. The peptides had the general formula (XY1XY2)3, with X representing hydrophobic amino acids (isoleucine (I) or leucine (L)), Y1 and Y2 representing cationic amino acids (arginine (R) or lysine (K)). The cytotoxicity of the designed ACPs in HCT 116 colorectal cancer, HeLa cervical cancer and human dermal fibroblast (HDF) cells was assessed by MTT test. The physicochemical properties of the peptides were characterized by various techniques including RP-HPLC, LC-MS, and Circular Dichroism (CD) spectroscopy. The surface activity of the peptides at the air-water interface and their interaction with the lipid monolayers as models for cell membranes were studied by Langmuir trough. The peptides consisting of I with R and K had selective anticancer activity while the combination of L and R diminished the anticancer activity of the peptides but rendered them more toxic to HDFs. The anticancer activity of the peptides was directed by their surface activity (amphiphilicity) and their secondary structure in hydrophobic surfaces including cancer cell membranes. The selectivity of the peptides for cancer cells was a result of their higher penetration into cancer cell membranes compared to normal cell membranes. The peptides exerted their anticancer activity by disrupting the mitochondrial membranes and eventually apoptosis. The results presented in this study provide an insight into the structure-activity relationship of this class of ACPs which can be employed as guidance to design new ACPs with improved anticancer activity and lower toxicity against normal cells.
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