Multiple N-methylation by a designed approach enhances receptor selectivity.
An unselective cyclic peptide integrin ligand was sequentially N-methylated by a designed approach, where only the externally oriented (solvent exposed) amide bonds were N-methylated. The N-methylation resulted in tremendous enhancement in selectivity among the different integrin receptor subtypes (alpha5beta1, alphavbeta3, and alphaIIbbeta3). Conformational and docking studies were performed, which suggested that the receptor selectivity is principally caused by reduced backbone flexibility due to N-methylation.
Chatterjee
Jayanta
J
Center for Integrated Protein Science at the Department Chemie, Lehrstuhl II für Organische Chemie, Technische Universität München, Lichtenbergstrasse 4, Garching D85747, Germany.
Ovadia
Oded
O
Zahn
Grit
G
Marinelli
Luciana
L
Hoffman
Amnon
A
Gilon
Chaim
C
Kessler
Horst
H
D001665:Binding Sites; D015195:Drug Design; D039081:Integrin alpha5beta1 / Q000737:chemistry*; D039302:Integrin alphaVbeta3 / Q000737:chemistry*; D008024:Ligands; D008745:Methylation; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry*; D013329:Structure-Activity Relationship
D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D008024:Ligands; D009842:Oligopeptides; D010456:Peptides, Cyclic; D019039:Platelet Glycoprotein GPIIb-IIIa Complex