Characteristic of neuraminidase inhibitory xanthones from Cudrania tricuspidata.
Natural polyphenolic compounds generally transpire to show relatively low inhibition against glycosidase including neuraminidase. In addition the inhibition modes of such compounds are rarely competitive. In this manuscript, a series of xanthone derivatives from Cudrania tricuspidata are shown to display nanomolar inhibitor activity against neuraminidase (EC 3.2.1.18) as well as competitive inhibition modes. Compound 8 bearing vicinal dihydroxy group on the A-ring displays nanomolar activity (IC(50)=0.08+/-0.01 microM), a 200-fold increase in activity relative to that of the first reported xanthone-derived neuraminidase inhibitor, mangiferin (IC(50)=16.2+/-4.2 microM). The 6,7-vicinal dihydroxy group plays a crucial role for inhibitory activity because compound 4, which has one of these hydroxyl groups prenylated was inactive (33% at 200 microM), whereas other compounds (1-3 and 6-8) showed nanomolar activity (0.08-0.27 microM) and competitive inhibition modes. Interestingly all inhibitors manifested enzyme isomerization inhibition against neuraminidase. The most potent inhibitor, compound 8 showed similar interaction with a transition-state analogue of neuraminic acid in active site.
Ryu
Young Bae
YB
Division of Applied Life Science (BK21 program), EB-NCRC, Institute of Agriculture and Life Science, Graduate School of Gyeongsang National University, Jinju 660-701, Republic of Korea.
Curtis-Long
Marcus J
MJ
Lee
Ji Won
JW
Kim
Jin Hyo
JH
Kim
Jun Young
JY
Kang
Kyu Young
KY
Lee
Woo Song
WS
Park
Ki Hun
KH
D020134:Catalytic Domain; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007700:Kinetics; D029586:Moraceae / Q000737:chemistry*; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018517:Plant Roots / Q000737:chemistry; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D044004:Xanthones; D009439:Neuraminidase