Flavonoids Derived from the Roots of Inhibit the Activity of SARS-CoV Papain-like Protease

Overview

Journal Plants (Basel)

Date 2024 Dec 17

PMID 39683112

Authors

Hyun Sim Woo

Kon Ho Lee

Ki Hun Park

Dae Wook Kim

Affiliations

Soon will be listed here.

Abstract

Despite the now infamous coronavirus disease outbreaks caused by severe acute respiratory syndrome coronavirus (SARS-CoV), this virus continues to be a threat to the global population. Although a huge research effort has targeted SARS-CoV, no report exists regarding natural small molecules targeting one of its key enzymes, papain-like protease (PLpro). In this study, nine flavonoids displaying SARS-CoV PLpro inhibitory activity were isolated from the root bark of . The compounds were identified as erythrabyssin II (), lespebuergine G4 (), 1-methoxyerythrabyssin II (), bicolosin A (), bicolosin B (), bicolosin (), xanthoangelol (), (±)-lespeol (), and parvisoflavanone (). Most compounds (- and -) inhibited SARS-CoV PLpro activity in a dose-dependent manner, with their s ranging from 5.56 to 75.37 μM. The structure-activity analysis of pterocarpans (-) showed that activity was enhanced by C1-OCH, but it was reduced by C8-CH. A mechanistic analysis revealed that all inhibitors were noncompetitive. Some of the key compounds isolated in this study are pterocarpans, which are abundantly present in the Leguminosae family. Overall, a rich source of SARS-CoV papain-like protease inhibitors was identified in this study.

References

Osipiuk J, Azizi S, Dvorkin S, Endres M, Jedrzejczak R, Jones K . Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors. Nat Commun. 2021; 12(1):743. PMC: 7854729. DOI: 10.1038/s41467-021-21060-3. View

Mori-Hongo M, Takimoto H, Katagiri T, Kimura M, Ikeda Y, Miyase T . Melanin synthesis inhibitors from Lespedeza floribunda. J Nat Prod. 2009; 72(2):194-203. DOI: 10.1021/np800395j. View

Sulea T, Lindner H, Purisima E, Menard R . Deubiquitination, a new function of the severe acute respiratory syndrome coronavirus papain-like protease?. J Virol. 2005; 79(7):4550-1. PMC: 1061586. DOI: 10.1128/JVI.79.7.4550-4551.2005. View

Ratia K, Saikatendu K, Santarsiero B, Barretto N, Baker S, Stevens R . Severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme. Proc Natl Acad Sci U S A. 2006; 103(15):5717-22. PMC: 1458639. DOI: 10.1073/pnas.0510851103. View

Ziebuhr J . The coronavirus replicase. Curr Top Microbiol Immunol. 2004; 287:57-94. PMC: 7121973. DOI: 10.1007/3-540-26765-4_3. View

Jayasinghe L, Rupasinghe G, Hara N, Fujimoto Y . Geranylated phenolic constituents from the fruits of Artocarpus nobilis. Phytochemistry. 2006; 67(13):1353-8. DOI: 10.1016/j.phytochem.2006.04.011. View

Palazzino G, Rasoanaivo P, Federici E, Nicoletti M, Galeffi C . Prenylated isoflavonoids from Millettia pervilleana. Phytochemistry. 2003; 63(4):471-4. DOI: 10.1016/s0031-9422(02)00489-2. View

Barretto N, Jukneliene D, Ratia K, Chen Z, Mesecar A, Baker S . The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity. J Virol. 2005; 79(24):15189-98. PMC: 1316023. DOI: 10.1128/JVI.79.24.15189-15198.2005. View

Ratia K, Pegan S, Takayama J, Sleeman K, Coughlin M, Baliji S . A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication. Proc Natl Acad Sci U S A. 2008; 105(42):16119-24. PMC: 2571001. DOI: 10.1073/pnas.0805240105. View

10.

Woo H, Kim D, Curtis-Long M, Lee B, Lee J, Kim J . Potent inhibition of bacterial neuraminidase activity by pterocarpans isolated from the roots of Lespedeza bicolor. Bioorg Med Chem Lett. 2011; 21(20):6100-3. DOI: 10.1016/j.bmcl.2011.08.046. View

11.

Devaraj S, Wang N, Chen Z, Chen Z, Tseng M, Barretto N . Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. J Biol Chem. 2007; 282(44):32208-21. PMC: 2756044. DOI: 10.1074/jbc.M704870200. View

12.

Rukachaisirikul T, Innok P, Suksamrarn A . Erythrina alkaloids and a pterocarpan from the bark of Erythrina subumbrans. J Nat Prod. 2008; 71(1):156-8. DOI: 10.1021/np070506w. View

13.

Maximov O, Kulesh N, Stepanenko L, Dmitrenok P . New prenylated isoflavanones and other constituents of Lespedeza bicolor. Fitoterapia. 2003; 75(1):96-8. DOI: 10.1016/j.fitote.2003.07.012. View

14.

Bradford M . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54. DOI: 10.1016/0003-2697(76)90527-3. View

15.

Tarbeeva D, Krylova N, Iunikhina O, Likhatskaya G, Kalinovskiy A, Grigorchuk V . Biologically active polyphenolic compounds from Lespedeza bicolor. Fitoterapia. 2022; 157:105121. DOI: 10.1016/j.fitote.2021.105121. View

16.

Tahir Ul Qamar M, Alqahtani S, Alamri M, Chen L . Structural basis of SARS-CoV-2 3CL and anti-COVID-19 drug discovery from medicinal plants. J Pharm Anal. 2020; 10(4):313-319. PMC: 7156227. DOI: 10.1016/j.jpha.2020.03.009. View

17.

Kiss L, Kurtan T, Antus S, Benyei A . Chiroptical properties and synthesis of enantiopure cis and trans pterocarpan skeleton. Chirality. 2003; 15(6):558-63. DOI: 10.1002/chir.10235. View

18.

Sami U . Methanolic extract from Lespedeza bicolor: potential candidates for natural antioxidant and anticancer agent. J Tradit Chin Med. 2020; 37(4):444-451. View

19.

Lee H, Kim S, Lim Y . Lespedeza bicolor extract supplementation reduced hyperglycemia-induced skeletal muscle damage by regulation of AMPK/SIRT/PGC1α-related energy metabolism in type 2 diabetic mice. Nutr Res. 2023; 110:1-13. DOI: 10.1016/j.nutres.2022.12.007. View

20.

Lindner H, Fotouhi-Ardakani N, Lytvyn V, Lachance P, Sulea T, Menard R . The papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme. J Virol. 2005; 79(24):15199-208. PMC: 1316033. DOI: 10.1128/JVI.79.24.15199-15208.2005. View