Rational design of anti-microbial peptides with enhanced activity and low cytotoxicity based on the structure of the arginine/histidine-rich peptide, chensinin-1

Abstract

Aims: To understand the structure-activity relationship of chensinin-1, a antimicrobial peptide (AMP) with an unusual structure, and to develop novel AMPs as therapeutic agents. Methods and Results: A series of chensinin-1 analogues were designed and synthesized by one to three replacement of glycines with leucines at the hydrophilic face of chensinin-1 or rearrangement of some of the residues in its sequence. Circular dichroism spectroscopy showed that the analogues adopted a-helical-type conformations in 50% trifluoroethanol/water but adopted b-strand-type conformations in 30 mmol l À1 sodium dodecyl sulphate. The anti-microbial activities of the peptides against Gram-positive bacteria increased 5-to 30-fold, and these increases paralleled the increases in the peptides' hydrophobicities. Their haemolytic activities also increased. Amphipathicities had little influence on the bactericidal activity of chensinin-1. All peptides caused leakage of calcein entrapped in negatively charged liposomes although with different efficiencies. The peptides did not induce leakage of calcein from uncharged liposomes. Conclusions: Peptide adopted an aperiodic structure can improve the antimicrobial potency by increasing peptide hydrophobicity. Its target is bacteria plasma membrane. Significance and Impact of the Study: Chensinin-1 can act as a new lead molecule for the study of AMPs with atypical structures.

Synthesis of analogs of peptides from Buthus martensii scorpion venom with potential antibiotic activity

“…Hodges and co-workers [6] also reports similar results for analogs of a 26-residue ␣-helical antimicrobial peptide. It is accepted that an increase in hydrophobicity for ␣-helix antimicrobial peptides results in an increase in both antimicrobial and hemolytic activities [14,22]. In our study we modified the analogs of BmKn1 by systematic substitution on positions 5 and 9 with alanine, valine and leucine, thereby increasing the hydrophobicity.…”

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

“…Chensinin-1 is a histidine rich peptide produced by the frog, Rana chensinensis and recent studies showed that low pH enhanced the positive charge of the peptide [31] and thereby, its ability to kill Gram-positive bacteria, such as Bacillus cereus [32]. This antibacterial activity appeared to involve the adoption of an extended structure, similar to that of other AMPs that are rich in specific residues [101,102], which induced lysis of the B. cereus membrane [32].…”

Insights into the membrane interaction mechanism and antibacterial properties of chensinin-1b

“…In the present study, chensinin-1b was designed and synthesised by the substitution of three Trp residues for Gly residues on the hydrophobic side, based on the amino acid sequence of chensinin-1a. CD spectroscopy showed that the a-helical content of chensinin-1b increased sharply from 4.45% in water to 28.06% in 50% TFE solution, and still exhibited a much lower a-helical content than that of Leu-substituted analogues, with 66.3% a-helix content [20]. By changing the primary structure, and because of the special characteristics of Trp residues, the antimicrobial activity of chensinin-1b has been greatly improved, especially against Gramnegative bacteria.…”

“…Importantly, chensinin-1 displays potent antimicrobial activity against Gram-positive bacteria, but has no haemolytic activity, and thus has potential as a novel antibiotic. In our previous study [20], a designed chensinin-1 analogue, chesinin-1a, in which its sequence was rearranged by adjusting its hydrophilic/polar residues on one face and its hydrophobic/nonpolar residues on the opposite face, is shown in the helical diagrams in Fig. 1.…”