Preparations of psi-peptide bond and peptide-aldehyde inhibitors of atrial granule serine proteinase, a candidate processing enzyme of pro-atrial 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 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.