Gramicidin S derivatives containing cis- and trans-morpholine amino acids (MAAs) as turn mimetics.
The cyclic decapeptide gramicidin S (GS) was used as a model for the evaluation of four turn mimetics. For this purpose, one of the D-Phe-Pro two-residue turn motifs in the rigid cyclic beta-hairpin structure of GS was replaced with morpholine amino acids (MAA 2-5), differing in stereochemistry and length of the side-chain. The conformational properties of the thus obtained GS analogues (6-9) was assessed by using NMR spectroscopy and X-ray crystallography, and correlated with their biological properties (antimicrobial and hemolytic activity). We show that compound 8, containing the dipeptide isostere trans-MAA 4, has an apparent high structural resemblance with GS and that its antibacterial activity against a panel of Gram positive and -negative bacterial strains is better than the derivatives 6, 7 and 9.
Kapoerchan
Varsha V
VV
Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Spalburg
Emile
E
de Neeling
Albert J
AJ
Mars-Groenendijk
Roos H
RH
Noort
Daan
D
Otero
José M
JM
Ferraces-Casais
Patricia
P
Llamas-Saiz
Antonio L
AL
van Raaij
Mark J
MJ
van Doorn
Joop
J
van der Marel
Gijs A
GA
Overkleeft
Herman S
HS
Overhand
Mark
M
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry*; D006096:Gramicidin / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000900:Anti-Bacterial Agents; D004151:Dipeptides; D009025:Morpholines; D006096:Gramicidin