Synthesis, biological activity and conformational analysis of head-to-tail cyclic analogues of LL37 and histatin 5.
LL37 and histatin 5 are antimicrobial peptides. LL37 exhibits killing activity against a broad spectrum of pathogens, whereas histatin 5 is primarily an antifungal agent. Head-to-tail cyclization of histatin 5 did not affect its antimicrobial and haemolytic activity. The cyclic LL37 exhibits identical antifungal and haemolytic activity as does LL37. Its antimicrobial activity varied in one dilution depending on the kind of bacteria. The structure of cyclic peptides was studied by circular dichroism spectroscopy. Both peptides undergo a conformational change leading to stabilisation of their α-helical structure in the presence of negatively charged sodium dodecyl sulfate micelles. However, with cyclic histatin 5, the presence of Zn(2+) ions is also necessary to fuse the peptide to the micelle. The specific action of the Zn(2+) ions is attributed to the presence of a zinc-binding motif, His-Glu-X-X-His. It has been speculated that this zinc complexing may be related to the well-established anticandidal activity. In the case of cyclic LL37, also the presence of a zwitterionic dodecylphosphocholine micelle induces formation of the helical structure. A microwave-assisted procedure for the cleavage of a peptide from the 2-chlorotrityl chloride resin was, for the first time, successfully used to obtain protected peptide fragments that can be applied to the preparation of head-to-tail cyclopeptides or to condensation of peptidic fragments.
University of Gdańsk, Faculty of Chemistry, Gdańsk, Poland. kamysz@chem.univ.gda.pl
Elżbieta
E
Kamysz
Emilia
E
Sikorska
Anna
A
Karafova
Małgorzata
M
Dawgul
D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry*; D002175:Candida / Q000187:drug effects; D002942:Circular Dichroism; D006461:Hemolysis / Q000187:drug effects; D054808:Histatins / Q000737:chemistry*; D006801:Humans; D008823:Micelles; D008872:Microwaves; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D054804:Cathelicidins
D000935:Antifungal Agents; D023181:Antimicrobial Cationic Peptides; D054808:Histatins; D008823:Micelles; D010456:Peptides, Cyclic; D012967:Sodium Dodecyl Sulfate; D054804:Cathelicidins