Inhibition of renin by angiotensinogen peptide fragments containing the hydroxy amino acid residue 5-amino-3-hydroxy-7-methyloctanoic acid.
The 3R,5S and 3S,5S diastereoisomers of the hydroxy amino acid 5-amino-3-hydroxy-7-methyloctanoic acid (AHMOA) were synthesized from L-leucine and then incorporated into various peptide fragments of angiotensinogen to give the following polypeptides: AHMOA-Val-Phe-OCH3, His-AHMOA-Val-Phe-OCH3, and AHMOA-Ile-His-OCH3. These compounds were tested in an in vitro renin assay system for their ability to inhibit either hog kidney renin or human amniotic renin. The most active analogue of the series was (3R,5S)-AHMOA-Val-Phe-OCH3 (16). Against hog kidney renin, this compound possessed a Ki = 1.7 X 10(-4) M, while against human amniotic fluid, 16 had a Ki = 0.95 X 10(-4) M. The analogues AHMOA-Val-Phe-OCH3 and His-AHMOA-Val-Phe-OCH3 exhibited noncompetitive kinetics when the 3R,5S isomer of AHMOA was employed and competitive kinetics when the 3S,5S diastereoisomer of AHMOA was used.
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis*; D000808:Angiotensinogen / Q000494:pharmacology*; D000809:Angiotensins / Q000494:pharmacology*; D000818:Animals; D007202:Indicators and Reagents; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009904:Optical Rotation; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D000092502:Renin Inhibitors
D000596:Amino Acids; D000808:Angiotensinogen; D000809:Angiotensins; D007202:Indicators and Reagents; D010446:Peptide Fragments; D010455:Peptides; D000092502:Renin Inhibitors; C039362:5-amino-3-hydroxy-7-methyloctanoic acid