Effect of ring size on conformation and biological activity of cyclic cationic antimicrobial peptides.
In a series of cyclic peptides based on GS10, an analogue of gramicidin S (GS), the ring size was varied from 10 to 16 amino acids. Alternative addition of basic and hydrophobic amino acids to the original GS10 construct generated a variety of even-numbered rings, i.e., GS10 [cyclo-(VKLdYPVKLdYP)], GS12 [cyclo-(VKLKdYPKVKLdYP)], GS14 [cyclo-(VKLKVdYPLKVKLdYP), and GS16 [cyclo-(VKLKVKdYPKLKVKLdYP)] (d stands for d-enantiomers). The odd-numbered analogues (11-, 13-, and 15-mers) were derived from these four peptides by either addition or deletion of single basic (Lys) or hydrophobic (Leu or Val) amino acids. The resulting peptides, divided into three groups on the basis of peptide ring size (10- to 12-meric, 13- and 14-meric, and 15- and 16-meric), illustrated a diverse spectrum of biological activity correlated to their ring size, degree of beta-structure disruption, charge, hydrophobicity, amphipathicity, and affinity for lipid membranes. Two of these peptides with potent antimicrobial activities and high therapeutic indexes (4.5- to 10-fold compared with GS) are promising candidates for development of broad-spectrum antibiotics.
Jelokhani-Niaraki
Masoud
M
Department of Chemistry, Wilfrid Laurier University, Waterloo, Ontario, Canada.
Kondejewski
Leslie H
LH
Wheaton
Laura C
LC
Hodges
Robert S
RS
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006096:Gramicidin / Q000737:chemistry; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007930:Leucine / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014633:Valine / Q000737:chemistry
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D023181:Antimicrobial Cationic Peptides; D010456:Peptides, Cyclic; D006096:Gramicidin; D007930:Leucine; D014633:Valine; D008239:Lysine