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.
|Number of pages||9|
|Journal||Biopolymers - Peptide Science Section|
|Publication status||Published - Jun 26 1999|
All Science Journal Classification (ASJC) codes
- Organic Chemistry