Open AccessChemical Synthesis of a Potent Antimicrobial Peptide Murepavadin Using a Tandem Native Chemical Ligation/Desulfurization Reaction
Author(s) -
Dipankar Chaudhuri,
Ganesan Rajasekaran,
Alicia Vogelaar,
Mansour A. Dughbaj,
Paul M. Beringer,
Julio A. Camarero
Publication year - 2021
Publication title -
journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.2
H-Index - 228
eISSN - 1520-6904
pISSN - 0022-3263
DOI - 10.1021/acs.joc.1c01858
Subject(s) - chemistry , native chemical ligation , combinatorial chemistry , chemical synthesis , chemical ligation , epimer , peptide , antimicrobial , residue (chemistry) , tandem , ligation , stereochemistry , organic chemistry , biochemistry , in vitro , materials science , composite material , microbiology and biotechnology , biology
Classical approaches for the backbone cyclization of polypeptides require conditions that may compromise the chirality of the C-terminal residue during the activation step of the cyclization reaction. Here, we describe an efficient epimerization-free approach for the Fmoc-based synthesis of murepavadin using intramolecular native chemical ligation in combination with a concomitant desulfurization reaction. Using this approach, bioactive murepavadin was produced in a good yield in two steps. The synthetic peptide antibiotic showed potent activity against different clinical isolates of P. aeruginosa . This approach can be easily adapted for the production of murepavadin analogues and other backbone-cyclized peptides.