title: Preparations of psi-peptide bond and peptide-aldehyde inhibitors of atrial granule serine proteinase, a candidate processing enzyme of pro-atrial natriuretic factor.
abstract: Pseudo-peptide bond inhibitors (psi-bond inhibitors) and peptide-aldehyde inhibitors of atrial granule serine proteinase, the candidate processing enzyme of pro-atrial natrieuretic factor, are prepared in high yield and purity by novel synthetic routes. The psi-bond compounds retain essential residues for enzyme binding, but place the enzyme inhibition site in the midst of the peptide sequence. Thus, Bz-APR-psi-LR and Bz-APR-psi-SLRR can be considered "readthrough inhibitors" of atrial granule serine proteinase. The most potent psi-peptide, Bz-APR-psi-SLRR (IC50=250 microM), is about fivefold less potent than the best peptide-aldehyde inhibitor (EACA-APR-CHO), and both the psi-bond and peptide-aldehyde compounds are competitive, reversible inhibitors of the enzyme. The psi-bond peptides containing two C-terminal Arg residues are three- to tenfold more potent than the analogous compounds containing only one C-terminal Arg residue, confirming the importance of both Arg residues in the enzyme processing recognition site. As expected, because of their moderate potencies, the psi-peptides are not useful affinity ligands for purification of atrial granule serine proteinase, but both peptide aldehydes are effective affinity ligands.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Virginia Commonwealth University, Medical College of Virginia, Richmond 23298-0614, USA.
authors.forename: A
authors.initials: A
authors.lastname: Damodaran
authors.forename: R B
authors.initials: RB
authors.lastname: Harris
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis* / Q000494:pharmacology*; D000595:Amino Acid Sequence; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000201:enzymology; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis*
chemical_list: D000447:Aldehydes; D010455:Peptides; D011498:Protein Precursors; D015842:Serine Proteinase Inhibitors; D009320:Atrial Natriuretic Factor; D012697:Serine Endopeptidases; C098098:atrial granule serine proteinase