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Synthesis of lucifensin by native chemical ligation and characteristics of its isomer having different disulfide bridge pattern
Author(s) -
Stanchev Stancho,
Zawada Zbigniew,
Monincová Lenka,
Bednárová Lucie,
Slaninová Jiřina,
Fučík Vladimír,
Čeřovský Václav
Publication year - 2014
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.2663
Subject(s) - disulfide bond , bridge (graph theory) , native chemical ligation , chemistry , combinatorial chemistry , stereochemistry , biochemistry , chemical synthesis , biology , anatomy , in vitro
The antimicrobial 40‐amino‐acid‐peptide lucifensin was synthesized by native chemical ligation (NCL) using N ‐acylbenzimidazolinone (Nbz) as a linker group. NCL is a method in which a peptide bond between two discreet peptide chains is created. This method has been applied to the synthesis of long peptides and proteins when solid‐phase synthesis is imcompatible. Two models of ligation were developed: [15 + 25] Ala‐Cys and [19 + 21] His‐Cys. The [19 + 21] His‐Cys method gives lower yield because of the lower stability of 18‐peptide‐His‐Nbz‐CONH 2 peptide, as suggested by density functional theory calculation. Acetamidomethyl‐deprotection and subsequent oxidation of the ligated linear lucifensin gave a mixture of lucifensin isomers, which differed in the location of their disulfide bridges only. The dominant isomer showed unnatural pairing of cysteines [C1−6], [C3−5], and [C2−4], which limits its ability to form α ‐helical structure. The activity of isomeric lucifensin toward Bacillus subtilis , Staphylococcus aureus , and Micrococcus luteus was lower than that of the natural lucifensin. The desired product native lucifensin was prepared from this isomer using a one‐pot reduction with dithiotreitol and subsequent air oxidation in slightly alkaline medium. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.