PREPARATIONS OF PSI-PEPTIDE BOND AND PEPTIDE-ALDEHYDE INHIBITORS OF ATRIAL GRANULE SERINE PROTEINASE, A CANDIDATE PROCESSING ENZYME OF PROATRIAL NATRIURETIC FACTOR

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 mu M), 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 [Damodaran and Harris (1995), J. Protein Chem., this issue].