Surface Physical Activity and Hydrophobicity of Designed Helical Peptide Amphiphiles Control Their Bioactivity and Cell Selectivity

Abstract

G(IIKK) 3 I-NH 2 (G3) has been recently shown to be highly effective at killing bacteria and inhibiting tumor cell growth while remaining benign to normal host mammalian cells.The aim of this work is to evaluate how residue substitutions of Ala (A), Val (V), Glu (E), and Lys (K) for the N-terminal Gly (G) or C-terminal Ile (I) of G3 affect the physiochemical properties and bioactivity of the variants. All substitutions caused the reduction of peptide hydrophobicity whilst N-terminal substitutions had less noticeable effect on the surface activity and helix-forming ability than C-terminal substitutions.N-terminal variants held potent antitumor activity but exhibited much lower hemolytic activity; these actions were related to the maintenance of their moderate surface pressures (12 to 16 mN/m) whilst their hydrophobicity was reduced. Thus, N-terminal substitutions enhanced the cell selectivity of the mutants relative to the control peptide G3. In contrast, C-terminal variants exhibited lower antitumor activity and further reduced hemolytic activity except for G(IIKK) 3 V-NH 2 . These features were also correlated well with their lower surface pressures (≤10 mN/m) and further decreased hydrophobicity. In spite of its very low helical content, the C-terminal variant G(IIKK) 3 V-NH 2 still displayed potent antitumor activity whilst retaining high hemolytic activity as well, again correlating well with its relatively high surface pressure and hydrophobicity. These results together indicated that surface activity governs the antitumor activity of the peptides but relative hydrophobicity influences their hemolytic activity. In contrast, helicity appears to be poorly correlated to their bioactivity. This work has demonstrated that N-terminal modifications provide a useful strategy to optimize the antitumor activity of helical anticancer peptides (ACPs) against its potential toxicity to mammalian host cells.

ACPred: A Computational Tool for the Prediction and Analysis of Anticancer Peptides

“…Moreover, the property of ARGP820103 (the fourth most important PCPs) is also associated with hydrophobicity property. Many previous studies have described the need for symbiosis between hydrophobicity and cationicity of peptides in order to enhance its cell penetrating property and its ability to reach target cell as to exert its effects [106,107,108,109]. In addition, researchers have made efforts to assess the influence of hydrophobicity on anticancer effects.…”

Improved prediction and characterization of anticancer activities of peptides using a novel flexible scoring card method

“…In the previous studies, the physicochemical properties (i.e. amino acid sequence, length, net charge, secondary structure, amphipathicity, and hydrophobicity) of peptides play crucial role in their hemolytic activity, penetration ability and anticancer/antitumor activity 1,19,[49][50][51][52] . The three importantly selected PCPs derived from iACP-FSCM consist of MITS020101 (Amphiphilicity index), QIAN88011 (Weights for alpha-helix at the window position of 6) and JOND750101 (Hydrophobicity) were showed in Table 6.…”

The Best Peptidomimetic Strategies to Undercover Antibacterial Peptides

“…Among them ( Figure 21 ), G3 is optimal with potent bioactivity (MIC E.coli (μM) = 8; MIC B. subtilis (μM) = 2) and low cytotoxicity (IC 50 (μM) = 15 (HeLa cells); = 25 HL60 cells) to the host mammalian cells. Hydrophobic modifications of G3 have been created by replacing the amino acid residues at the peptide N-terminals or C-terminals or the side chains [ 210 , 211 ]. The high selectivity and associated features are attributed to two design tactics: the use of Ile residues rather than Leu and the perturbation of the hydrophobic face of the helical structure with the insertion of a positively charged Lys residue.…”