Plant phenolics as prolyl endopeptidase inhibitors.
Prolyl endopeptidase (PEP, EC 3.4.21.26), a serine protease, is widely distributed in various organs, particularly in the brains of Alzheimer's disease patients. The expression of PEP in Alzheimer's patients has been found to be significantly higher than that of the normal person, suggesting that a specific PEP inhibitor can be a good candidate for an anti-amnestic drug. In the current study, thirty-nine plant phenolics were investigated to determine their roles as prolyl endopeptidase (PEP) inhibitors. Nineteen compounds such as 1,2,3-trigalloyl glucopyranoside, 1,2,6-trigalloyl glucopyranoside, 1,2,3,4,6-pentagalloyl gluco-pyranoside, 1,2,6-trigalloyl alloside, 1,3,6-trigalloyl alloside, 1,2,3,6-tetragalloyl alloside, acetonyl geraniin, corilagin, elaeocarpusin, euphorscopin, geraniin, helioscopin B, helioscopinin A, helioscopinin B, jolkinin, macranganin, rugosin E, supinanin, and teracatain exhibited strong inhibition against PEP (IC50 26.7 - 443.7 x 10(-9) M). Rugosin E (IC50 26.7 x 10(-9) M) showed the most effective inhibition followed by 1,2,6-trigalloyl glucopyranoside (IC5031.4 x 10(-9) M) and macranganin (IC5042.6 x 10(-9) M). No significant structure-activity relationship was found; however, at least, three pyrogallol groups seem to be a minimal requirement for stronger activity against PEP All 19 active compounds inhibited PEP in a non-competitive mode with a substrate in Dixon plots. They did not show significant effects against other serine proteases such as trypsin, chymotrypsin and elastase, indicating that they were relatively specific PEP inhibitors.
Lee
Seung-Ho
SH
College of Agriculture & Life Sciences, Kyungpook National University, Daegu 702-701, Korea.
Jun
Mira
M
Choi
Ji-Young
JY
Yang
Eun-Ju
EJ
Hur
Jong-Moon
JM
Bae
KiHwan
K
Seong
Yeon-Hee
YH
Huh
Tae-Lin
TL
Song
Kyung-Sik
KS
D000544:Alzheimer Disease / Q000201:enzymology; D019665:Euphorbiaceae / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010636:Phenols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013329:Structure-Activity Relationship
D010636:Phenols; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases