D-tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A2 (IIa) with antiinflammatory activity
Author(s)
Hansford, KA
Reid, RC
Clark, CI
Tyndall, JDA
Whitehouse, MW
Guthrie, T
McGeary, RP
Schafer, K
Martin, JL
Fairlie, DP
Griffith University Author(s)
Year published
2003
Metadata
Show full item recordAbstract
Few reported inhibitors of secretory phospholipase A2enzymes truly inhibit the IIa human isoform (hnpsPLA2-IIa) noncovalently at submicromolar concentrations. Herein, the simple chiral precursor D-tyrosine was derivatised to give a series of potent new inhibitors of hnpsPLA2-IIa. A 2.2-Å crystal structure shows an inhibitor bound in the active site of the enzyme, chelated to a Ca2+ion through carboxylate and amide oxygen atoms, H-bonded through an amide NH group to His48, with multiple hydrophobic contacts and a T-shaped aromatic-group–His6 interaction. Antiinflammatory activity is also demonstrated for two compounds ...
View more >Few reported inhibitors of secretory phospholipase A2enzymes truly inhibit the IIa human isoform (hnpsPLA2-IIa) noncovalently at submicromolar concentrations. Herein, the simple chiral precursor D-tyrosine was derivatised to give a series of potent new inhibitors of hnpsPLA2-IIa. A 2.2-Å crystal structure shows an inhibitor bound in the active site of the enzyme, chelated to a Ca2+ion through carboxylate and amide oxygen atoms, H-bonded through an amide NH group to His48, with multiple hydrophobic contacts and a T-shaped aromatic-group–His6 interaction. Antiinflammatory activity is also demonstrated for two compounds administered orally to rats.
View less >
View more >Few reported inhibitors of secretory phospholipase A2enzymes truly inhibit the IIa human isoform (hnpsPLA2-IIa) noncovalently at submicromolar concentrations. Herein, the simple chiral precursor D-tyrosine was derivatised to give a series of potent new inhibitors of hnpsPLA2-IIa. A 2.2-Å crystal structure shows an inhibitor bound in the active site of the enzyme, chelated to a Ca2+ion through carboxylate and amide oxygen atoms, H-bonded through an amide NH group to His48, with multiple hydrophobic contacts and a T-shaped aromatic-group–His6 interaction. Antiinflammatory activity is also demonstrated for two compounds administered orally to rats.
View less >
Journal Title
ChemBioChem
Volume
4
Issue
2-3
Subject
Medicinal and biomolecular chemistry
Medicinal and biomolecular chemistry not elsewhere classified
Biochemistry and cell biology