Design of serine protease inhibitors with conformation restricted by amino acid side-chain-side-chain CH/π interaction

Yasuyuki Shimohigashi, Takeru Nose, Yasuko Yamauchi, Iori Maeda

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

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/π interaction. Their spatial proximity was evidenced by 400 MHz1 H-nmr measurements, observing large upfield shifts of proton signals of D-Xaa- alkyl and nuclear Overhauser effect (NOE) enhancements between the D-Xaa- alkyl and Phe-phenyl groups. This conformational restriction brought by CH/π 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 γ-chymotrypsin. Detailed structure-activity studies have substantiated the structure of dipeptides in the active center of the enzyme.

Original languageEnglish
Pages (from-to)9-17
Number of pages9
JournalBiopolymers - Peptide Science Section
Volume51
Issue number1
DOIs
Publication statusPublished - Jun 26 1999

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Biomaterials
  • Organic Chemistry

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