Plant phenolics as prolyl endopeptidase inhibitors

• Published in: Archives of pharmacal research 2007, 30(7), , pp.827-833
• Main Authors: Lee, Seung -Ho, Jun, Mira, Choi, Ji -Young, Yang, Eun -Ju, Hur, Jong -Moon, Bae, KiHwan, Seong, Yeon -Hee, Huh, Tae -Lin, Song, Kyung -Sik
• Format: Article
• Language: English
• Subjects: Alzheimer disease; Alzheimer Disease - enzymology; chymotrypsin; drugs; elastase; Euphorbiaceae - chemistry; inhibition; Inhibitory Concentration 50; Molecular Structure; patients; Phenols - chemistry; Phenols - isolation & purification; Phenols - pharmacology; proteases; pyrogallol; serine; Serine Endopeptidases - metabolism; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - isolation & purification; Serine Proteinase Inhibitors - pharmacology; Structure-Activity Relationship; structure-activity relationships; trypsin; 약학
• ISSN: 0253-6269; 1976-3786
• DOI: 10.1007/BF02978832

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 - 443.7x10⁻⁹ M). Rugosin E (IC₅₀ 26.7x10⁻⁹ M) showed the most effective inhibition followed by 1,2,6-trigalloyl glucopyranoside (IC₅₀31.4x10⁻⁹ M) and macranganin (IC₅₀ 42.6x10⁻⁹ 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.