Design of serine protease inhibitors with conformation restricted by amino acid side-chain-side-chain CH/pie interaction.
A novel type of conformationally restricted peptides with the structure of H-D-Xaa-Phe-NH-CH2-C6H5 has been developed as inhibitors of serine proteinase chymotrypsin. The D-Xaa-alkyl and Phe-phenyl groups resulted in a formation of the hydrophobic core due to the side-chain-side-chain CH/pie interaction. Their spatial proximity was evidenced by 400 MHz 1H-nmr measurements, observing large upfield shifts of proton signals of D-Xaa-alkyl and nuclear Over-hauser effect (NOE) enhancements between the D-Xaa-alkyl and Phe-phenyl groups. This conformational restriction brought by CH/pie interaction produced an inhibitory structure, in which the C-terminal amide-benzyl group fits the chymotrypsin S1 site and the hydrophobic core binds to the S2 site. The inhibitory conformation was demonstrated crystallographically for the complex between the dipeptide H-D-Leu-Phe-NH-CH2-C6H4(p-F) and gamma-chymotrypsin. Detailed structure-activity studies have substantiated the structure of dipeptides in the active center of the enzyme.
Shimohigashi
Y
Y
Department of Chemistry, Faculty of Science, Kyushu University, Fukuoka, Japan. shimoscc@mbox.nc.kyushu-u.ac.jp
Nose
T
T
Yamauchi
Y
Y
Maeda
I
I
D001665:Binding Sites; D002918:Chymotrypsin / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D011487:Protein Conformation; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D004151:Dipeptides; D015842:Serine Proteinase Inhibitors; D002918:Chymotrypsin