Biflavonoids from Torreya nucifera displaying SARS-CoV 3CLpro inhibition

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 22; pp. 7940 - 7947
• Main Authors: YOUNG BAE RYU, HYUNG JAE JEONG, RHO, Mun-Chual, WOO SONG LEE, JANG HOON KIM, YOUNG MIN KIM, PARK, Ji-Young, KIM, Doman, NAGUYEN, Thi Thanh Hanh, PARK, Su-Jin, JONG SUN CHANG, KI HUN PARK
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 15.11.2010; Elsevier Ltd
• Subjects: Biological and medical sciences; General pharmacology; Medical sciences; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Asia; Cysteine endopeptidases; Torreya nucifera; Flavonoid; Modeling; Medicinal plant; Folk medicine; Structure activity relation; Severe acute respiratory syndrome virus; Gymnospermae; Molecular model; Antiviral; Coronaviridae; SARS-CoV 3CL; Enzyme; Pharmacognosy; Oriental medicine; Enzyme inhibitor; Biflavonoid; Inhibitor enzyme complex; In vitro; Virus; Amentoflavone; Peptidases; Coronavirus; Plant origin; Flavone derivatives; Hydrolases; Isolation; Spermatophyta; Coniferales; Nidovirales
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.09.035

Inhibitory activity appeared to be associated with the presence of an apigenin moiety at position C-3′ of flavones, as biflavonoid had an effect on SARS-CoV 3CL pro inhibitory activity. As part of our search for botanical sources of SARS-CoV 3CL pro inhibitors, we selected Torreya nucifera , which is traditionally used as a medicinal plant in Asia. The ethanol extract of T. nucifera leaves exhibited good SARS-CoV 3CL pro inhibitory activity (62% at 100 μg/mL). Following bioactivity-guided fractionation, eight diterpenoids ( 1 – 8 ) and four biflavonoids ( 9 – 12 ) were isolated and evaluated for SARS-CoV 3CL pro inhibition using fluorescence resonance energy transfer analysis. Of these compounds, the biflavone amentoflavone ( 9 ) (IC 50  = 8.3 μM) showed most potent 3CL pro inhibitory effect. Three additional authentic flavones (apigenin, luteolin and quercetin) were tested to establish the basic structure–activity relationship of biflavones. Apigenin, luteolin, and quercetin inhibited 3CL pro activity with IC 50 values of 280.8, 20.2, and 23.8 μM, respectively. Values of binding energy obtained in a molecular docking study supported the results of enzymatic assays. More potent activity appeared to be associated with the presence of an apigenin moiety at position C-3′ of flavones, as biflavone had an effect on 3CL pro inhibitory activity.