Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa

• Published in: Bioorganic & medicinal chemistry Vol. 21; no. 11; pp. 3051 - 3057
• Main Authors: Cho, Jung Keun, Curtis-Long, Marcus J., Lee, Kon Ho, Kim, Dae Wook, Ryu, Hyung Won, Yuk, Heung Joo, Park, Ki Hun
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.06.2013; Elsevier; Elsevier Ltd. Published by Elsevier Ltd
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - isolation & purification; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; chemotypes; Coronavirus 3C Proteases; Cysteine Endopeptidases - chemistry; Escherichia coli - genetics; flavonoids; Flavonoids - chemistry; Flavonoids - isolation & purification; Fruit - chemistry; fruits; Geranylated flavonoids; inhibitory concentration 50; Kinetics; Life Sciences & Biomedicine; Magnoliopsida - chemistry; nuclear magnetic resonance spectroscopy; Paulownia; Paulownia tomentosa; Pharmacology & Pharmacy; phenol; Physical Sciences; Plant Extracts - chemistry; PLpro inhibitor; proteinases; Recombinant Proteins - chemistry; SARS coronavirus; SARS-CoV PLpro; Science & Technology; Severe acute respiratory syndrome coronavirus; Severe acute respiratory syndrome-related coronavirus - enzymology; trees; Viral Proteins - antagonists & inhibitors; Viral Proteins - chemistry; virus replication; SARS-CoV PLpro; Km; PLpro inhibitor; IC50; Paulownia tomentosa; Geranylated flavonoids; Ki; FLAVANONES; BATS; VIRUS; RESPIRATORY SYNDROME CORONAVIRUS
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2013.03.027

A series of geranylated flavonoids 1–12 demostrated a high inhibition against SARS-CoV pain like protease. The flavonoids 1–5 were identified as new compounds and have very rare functionality, 3,4-dihydro-2H-pyran. SARS-CoV papain-like protease (PLpro) is an important antiviral target due to its key roles in SARS virus replication. The MeOH extracts of the fruits of the Paulownia tree yielded many small molecules capable of targeting PLpro. Five of these compounds were new geranylated flavonoids, tomentin A, tomentin B, tomentin C, tomentin D, tomentin E (1–5). Structure analysis of new compounds (1–5) by NMR showed that they all contain a 3,4-dihydro-2H-pyran moiety. This chemotype is very rare and is derived from cyclization of a geranyl group with a phenol functionality. Most compounds (1–12) inhibited PLpro in a dose dependent manner with IC50’s raging between 5.0 and 14.4μM. All new compounds having the dihydro-2H-pyran group showed better inhibition than their parent compounds (1 vs 11, 2 vs 9, 4 vs 12, 5 vs 6). In kinetic studies, 1–12 emerged to be reversible, mixed inhibitors.