Structure/function relationships in the inhibition of thimet oligopeptidase by carboxyphenylpropyl-peptides.
Some novel N-[1(RS)-carboxy-3-phenylpropyl]tripeptide p-aminobenzoates have been synthesised as inhibitors of thimet oligopeptidase (EC 3.4.24.15). These compounds are considered to bind as substrate analogues with the Cpp group in S1 and the peptide portion in the S' sites. The most potent inhibitor is Cpp-Ala-Pro-Phe-pAb, which has a Ki = 7 nM. Substitution of Gly for Ala at P1' leads to weaker binding which can be ascribed to increased rotational freedom. Good substrates often have Pro at P2' and Pro is favoured over Ala at this position in the inhibitors, too. When P2' is Pro, Phe is preferred over Tyr and Trp in P3'. The p-aminobenzoate group makes an important contribution to the binding, probably by forming a salt bridge, and removal of the C-terminal negative charge results in much less potent inhibitors.
Knight
C G
CG
Department of Biochemistry, Strangeways Research Laboratory, Cambridge, UK.
Barrett
A J
AJ
D000409:Alanine; D000595:Amino Acid Sequence; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011392:Proline; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D010455:Peptides; D011392:Proline; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase; D000409:Alanine