Analysis of flavonoid-based pharmacophores that inhibit aggrecanases (ADAMTS-4 and ADAMTS-5) and matrix metalloproteinases through the use of topologically constrained peptide substrates.
Polyphenolic natural products from green tea and red wine have been identified as metalloproteinase inhibitors. Members from the flavonoid and stilbene families found to possess metalloproteinase inhibitory activities include (-)-epigallocatechin gallate, (-)-epicatechin gallate and piceatannol, but their minimally active pharmacophores have not been evaluated. The present study has examined compounds that are structural components of or structurally related to (-)-epigallocatechin gallate, (-)-epicatechin gallate and piceatannol for inhibition of aggrecanases and four representative matrix metalloproteinases. Piceatannol and pyrogallol were found to inhibit all aggrecanases and matrix metalloproteinases studied, indicating a crucial reliance on multiple hydroxyl groups for (-)-epigallocatechin gallate, (-)-epicatechin gallate and piceatannol activity. Differences in K(i) values for pyrogallol as determined with two structurally distinct substrates indicated the likelihood that this compound binds in a non-competitive modality. Further analysis showed that pyrogallol acts as an exosite inhibitor, consistent with the action of (-)-epigallocatechin gallate. In contrast, piceatannol was shown to be a competitive binding inhibitor and showed no differences in apparent K(i) values as determined by distinct substrates, illustrating the benefits of using two structurally distinct substrates to assist the analysis of protease inhibitors. The compounds identified here could be utilized to develop novel metalloproteinase probes or as fragment components of more active inhibitors.
Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, 33431, USA.
Mare
M
Cudic
Gayle D
GD
Burstein
Gregg B
GB
Fields
Janelle
J
Lauer-Fields
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D000595:Amino Acid Sequence; D000975:Antioxidants / Q000737:chemistry; D002392:Catechin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D011348:Procollagen N-Endopeptidase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology
D000975:Antioxidants; D004791:Enzyme Inhibitors; D005419:Flavonoids; D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D013267:Stilbenes; C041525:3,3',4,5'-tetrahydroxystilbene; D002392:Catechin; C045651:epigallocatechin gallate; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D020782:Matrix Metalloproteinases; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human