Synthetic and enzyme inhibition studies of pepstatin analogues containing hydroxyethylene and ketomethylene dipeptide isosteres.
Synthetic details for the preparation of a series of hydroxyethylene and ketomethylene dipeptide isosteres with control of stereochemistry at C(2) are described. Incorporation of the isosteres into peptide sequences derived from pepstatin afforded potent inhibitors of the aspartic protease porcine pepsin. When Leu-OH-Ala or Leu-OH-Phe was substituted for statine [3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid), inhibitors equipotent to the parent compound were obtained, whereas Leu-OH-Gly was a much less effective replacement for statine. A similar trend was evident in the corresponding ketones. The finding that structural features for good substrates do not closely parallel those for good inhibitors is discussed.
D000595:Amino Acid Sequence; D000818:Animals; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000138:chemical synthesis*; D010434:Pepsin A / Q000037:antagonists & inhibitors*; D010436:Pepstatins / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine
D004151:Dipeptides; D007202:Indicators and Reagents; D009842:Oligopeptides; D010436:Pepstatins; D010434:Pepsin A