Inhibition of cathepsin D by substrate analogues containing statine and by analogues of pepstatin.
Five new cathepsin D inhibitors were synthesized and tested as inhibitors of bovine cathepsin D. The compounds were derived by replacing a Phe-Phe dipeptidyl unit of a good cathepsin D substrate, Boc-Phe-Leu-Ala-Phe-Phe-Val-Leu-OR, with statine [3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, Sta) or with Sta-Phe. The best inhibitor, Boc-Phe-Leu-Ala-(S,S)-Sta-Val-Leu-OMe, inhibited cathepsin D with a Ki value of 1.1 nM. In general, the more effective inhibitors were consistent with the proposal that statine functions as a replacement for a dipeptidyl unit. Thirty-five known pepstatin analogues also were evaluated as cathepsin D inhibitors. Substituents in the P4 and P3' positions are important for maximal inhibition of this aspartic proteinase, and the P4 substituent appears more important for inhibition of cathepsin D than for inhibition of other aspartic proteinases.
D000595:Amino Acid Sequence; D000596:Amino Acids; D000818:Animals; D002402:Cathepsin D / Q000037:antagonists & inhibitors*; D002417:Cattle; D007202:Indicators and Reagents; D007700:Kinetics; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D010436:Pepstatins / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000596:Amino Acids; D007202:Indicators and Reagents; D009842:Oligopeptides; D010436:Pepstatins; D002402:Cathepsin D; C013165:statine