Peptide aldehyde inhibitors of the kallikreins: an investigation of subsite interactions with tripeptides containing structural variations at the amino terminus

• Published in: The journal of peptide research Vol. 52; no. 1; pp. 60 - 71
• Main Authors: Garrett, GS, Correa, PE, McPhail, SJ, Tornheim, K, Burton, JA, Eickhoff, DJ, Engerholm, GG, McIver, JM
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.07.1998
• Subjects: Aldehydes - pharmacology; Animals; Binding Sites - physiology; Biochemical Research Methods; Biochemistry & Molecular Biology; Blood Proteins - metabolism; Humans; Kallikreins - antagonists & inhibitors; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Molecular Structure; Pancreas - enzymology; Peptides - chemistry; Science & Technology; Serine Proteinase Inhibitors - chemical synthesis; Swine; enzyme; TISSUE KALLIKREIN; peptide; PLASMA KALLIKREIN; COMPLEX; LEUPEPTIN ANALOGS; ANALOG INHIBITORS; BOVINE TRYPSIN; aldehyde; RAY CRYSTAL-STRUCTURE; inhibitor; SERINE; kallikrein; SELECTIVE INHIBITORS; BINDING
• ISSN: 1397-002X
• DOI: 10.1111/j.1399-3011.1998.tb00653.x

A series of tripeptide aldehyde derivatives containing variations at the P3 subsite and the amino terminus has been prepared and evaluated for trypsin-like serine protease inhibition. These compounds exhibit strong in vitro inhibition of human plasma kallikrein (HPK), porcine pancreatic kallikrein (PPK) and human plasmin (HP). As suspected from an examination of a related crystal structure, the presence of a hydrophobic residue (adamantyl) at the amino terminus dramatically improves the binding to PPK. The adamantyl group, however, represents a peak in binding; larger residues cause the binding to be reduced, and thus are less well accommodated in this subsite. Although both HP and HPK also can accept large molecular volume at the amino terminus, they do not exhibit the same preference for large residues at this subsite that is demonstrated by PPK. Selectivity differences also are observed with P3 subsite substitution; with PPK preferring a bulky, but compact side-chain (t-butyl) and HP and HPK preferring a more extended (e.g. benzyl) group.