Synthesis of nisin AB dicarba analogs using ring-closing metathesis: influence of sp(3) versus sp(2) hybridization of the α-carbon atom of residues dehydrobutyrine-2 and dehydroalanine-5 on the lipid II binding affinity.
Herein the synthesis of two nisin AB dicarba analogs is described, focusing on amino acid modifications at positions 2 and 5. The nisin mimics were synthesized by a combination of solid phase synthesis of the linear peptides, followed by macrocyclization via ring-closing metathesis and fragment assembly by means of solution phase chemistry. The two N-terminal nisin AB-fragment mimics contain either the native dehydrobutyrine (Dhb)/dehydroalanine (Dha) amino acid residues or alanine at position 2 and 5, respectively. The native dehydrobutyrine at position 2 and dehydroalanine at position 5 were introduced as their precursors, namely threonine and serine, respectively, and subsequent dehydration was carried out by EDCI/CuCl as the condensing agent. Both AB-fragment mimics were analyzed in a lipid II binding assay and it was found that the Ala2/Ala5 AB-mimic (2) showed a reduced activity, while the Dhb2/Dha5 AB-mimic (3) was as active as the native AB-fragment (1).
Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands. D.T.S.Rijkers@uu.nl.
Jack C
JC
Slootweg
Eric F
EF
van Herwerden
Mark F M
MF
van Doremalen
Eefjan
E
Breukink
Rob M J
RM
Liskamp
Dirk T S
DT
Rijkers
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D000613:Aminobutyrates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009561:Nisin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D053835:Unilamellar Liposomes / Q000378:metabolism; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000378:metabolism
D000613:Aminobutyrates; D000900:Anti-Bacterial Agents; D053835:Unilamellar Liposomes; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; D009561:Nisin; C088694:dehydrobutyrine; C015102:dehydroalanine; C102526:nisin A; D000409:Alanine