Utilization of an amphipathic leucine zipper sequence to design antibacterial peptides with simultaneous modulation of toxic activity against human red blood cells.
The toxicity of naturally occurring or designed antimicrobial peptides is a major barrier for converting them into drugs. To synthesize antimicrobial peptides with reduced toxicity, several amphipathic peptides were designed based on the leucine zipper sequence. The first one was a leucine zipper peptide (LZP); in others, leucine residues at the a- and/or d-position were substituted with single or double alanine residues. The results showed that LZP and its analogs exhibited appreciable and similar antibacterial activity against the tested gram-positive and gram-negative bacteria. However, the substitution of alanine progressively lowered the toxicity of LZP against human red blood cells (hRBCs). The substitution of leucine with alanine impaired the binding and localization of LZP to hRBCs, but had little effect on the peptide-induced damage of Escherichia coli cells. Although LZP and its analogs exhibited similar permeability, secondary structures, and localization in negatively charged membranes, significant differences were observed among these peptides in zwitterionic membranes. The results suggest a novel approach for designing antibacterial peptides with modulation of toxicity against hRBCs by employing the leucine zipper sequence. Also, to the best of our knowledge, the results demonstrate that this sequence could be utilized to design novel cell-selective molecules for the first time.
Ahmad
Aqeel
A
Molecular and Structural Biology Division, University of Oxford, Oxford OX3 7LD, United Kingdom.
Yadav
Sharada Prasad
SP
Molecular and Structural Biology Division, University of Oxford, Oxford OX3 7LD, United Kingdom.
Asthana
Neeta
N
Molecular and Structural Biology Division, University of Oxford, Oxford OX3 7LD, United Kingdom.
Mitra
Kalyan
K
Electron Microscopy Unit, Central Drug Research Institute, Lucknow 226 001, India.
Srivastava
Swati Prakash
SP
Molecular and Structural Biology Division, University of Oxford, Oxford OX3 7LD, United Kingdom.
Ghosh
Jimut Kanti
JK
Molecular and Structural Biology Division, University of Oxford, Oxford OX3 7LD, United Kingdom. Electronic address: jighosh@yahoo.com.
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002463:Cell Membrane Permeability / Q000187:drug effects; D015195:Drug Design; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D016350:Leucine Zippers; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D009842:Oligopeptides