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Volume 38 Issue 3
June 2023
    Citation: Zherui Zhang, Hongqing Zhang, Yanan Zhang, Qiuyan Zhang, Qiaojie Liu, Yanyan Hu, Xiaoling Chen, Jing Wang, Yujia Shi, Chenglin Deng, Peng Gong, Bo Zhang, Xiaodan Li, Bing Zhu, Hanqing Ye. Oridonin inhibits SARS-CoV-2 replication by targeting viral proteinase and polymerase .VIROLOGICA SINICA, 2023, 38(3) : 470-479.  http://dx.doi.org/10.1016/j.virs.2023.04.008
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    Oridonin inhibits SARS-CoV-2 replication by targeting viral proteinase and polymerase

    • a. Virus Laboratory, Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China;

    • b. Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China;

    • c. University of Chinese Academy of Sciences, Beijing, 100049, China;

    • d. Hunan Normal University, School of Medicine, Changsha, 410081, China

    • COVID-19 has become a global public health crisis since its outbreak in China in December 2019. Currently there are few clinically effective drugs to combat SARS-CoV-2 infection. The main protein (Mpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 are involved in the viral replication, and might be prospective targets for anti-coronavirus drug development. Here, we investigated the antiviral activity of oridonin, a natural small-molecule compound, against SARS-CoV-2 infection in vitro. The time-of-addition analysis showed that oridonin efficiently inhibited SARS-CoV-2 infection by interfering with the genome replication at the post-entry stage. Mechanistically, the inhibition of viral replication by oridonin depends on the oxidation activity of α, β-unsaturated carbonyl. Further experiments showed that oridonin not only effectively inhibited SARS-CoV-2 Mpro activity, but also had some inhibitory effects on PLpro-mediated deubiquitinating and viral polymerase-catalyzed RNA elongation activities at high concentrations. In particular, oridonin could inhibit the bat SARS-like CoV and the newly emerged SARS-CoV-2 omicron variants (BA.1 and BA.2), which highlights its potential as a pan-coronavirus antiviral agent. Overall, our data provide strong evidence that oridonin is an efficient antiviral agent against SARS-CoV-2 infection.
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      1. Amporndanai, K., Meng, X., Shang, W., Jin, Z., Rogers, M., Zhao, Y., Rao, Z., Liu, Z.J., Yang, H., Zhang, L., O'neill, P.M., Samar Hasnain, S., 2021. Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives. Nat Commun. 12, 3061.

      2. Chopra, B., Dhingra, A.K., 2021. Natural products:A lead for drug discovery and development. Phytother Res. 35, 4660-4702.

      3. Cuadrado, A., Pajares, M., Benito, C., Jimenez-Villegas, J., Escoll, M., Fernandez-Gines, R., Garcia Yague, A.J., Lastra, D., Manda, G., Rojo, A.I., Dinkova-Kostova, A.T., 2020. Can Activation of NRF2 Be a Strategy against COVID-19? Trends Pharmacol Sci. 41, 598-610.

      4. Dai, W., Zhang, B., Jiang, X.M., Su, H., Li, J., Zhao, Y., Xie, X., Jin, Z., Peng, J., Liu, F., Li, C., Li, Y., Bai, F., Wang, H., Cheng, X., Cen, X., Hu, S., Yang, X., Wang, J., Liu, X., Xiao, G., Jiang, H., Rao, Z., Zhang, L.K., Xu, Y., Yang, H., Liu, H., 2020. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science 368, 1331-1335.

      5. Freitas, B.T., Durie, I.A., Murray, J., Longo, J.E., Miller, H.C., Crich, D., Hogan, R.J., Tripp, R.A., Pegan, S.D., 2020. Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease. ACS Infect Dis, 6, 2099-2109.

      6. Fu, L., Ye, F., Feng, Y., Yu, F., Wang, Q., Wu, Y., Zhao, C., Sun, H., Huang, B., Niu, P., Song, H., Shi, Y., Li, X., Tan, W., Qi, J., Gao, G.F., 2020. Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease. Nat Commun. 11, 4417.

      7. Fujita, E., Nagao, Y., Kaneko, K., Nakazawa, S., Kuroda, H., 1976. The antitumor and antibacterial activity of the Isodon diterpenoids. Chem Pharm Bull. (Tokyo) 24, 2118-2127.

      8. Gyebi, G.A., Ogunro, O.B., Adegunloye, A.P., Ogunyemi, O.M., Afolabi, S.O., 2021. Potential inhibitors of coronavirus 3-chymotrypsin-like protease (3CL(pro)):an in silico screening of alkaloids and terpenoids from African medicinal plants. J Biomol Struct Dyn. 39, 3396-3408.

      9. He, H., Jiang, H., Chen, Y., Ye, J., Wang, A., Wang, C., Liu, Q., Liang, G., Deng, X., Jiang, W., Zhou, R., 2018. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nat Commun. 9, 2550.

      10. Huang, H., Weng, H., Dong, B., Zhao, P., Zhou, H., Qu, L., 2017. Oridonin Triggers Chaperon-mediated Proteasomal Degradation of BCR-ABL in Leukemia. Sci Rep. 7, 41525.

      11. Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., Peng, C., Duan, Y., Yu, J., Wang, L., Yang, K., Liu, F., Jiang, R., Yang, X., You, T., Liu, X., Yang, X., Bai, F., Liu, H., Liu, X., Guddat, L.W., Xu, W., Xiao, G., Qin, C., Shi, Z., Jiang, H., Rao, Z., Yang, H., 2020. Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors. Nature 582, 289-293.

      12. Kumar, S.B., Krishna, S., Pradeep, S., Mathews, D.E., Pattabiraman, R., Murahari, M., Murthy, T.P.K., 2021. Screening of natural compounds from Cyperus rotundus Linn against SARS-CoV-2 main protease (M(pro)):An integrated computational approach. Comput Biol Med. 134, 104524.

      13. Littler, D.R., Liu, M., Mcauley, J.L., Lowery, S.A., Illing, P.T., Gully, B.S., Purcell, A.W., Chandrashekaran, I.R., Perlman, S., Purcell, D.F.J., Quinn, R.J., Rossjohn, J., 2021. A natural product compound inhibits coronaviral replication in vitro by binding to the conserved Nsp9 SARS-CoV-2 protein. J Biol Chem 297. 101362.

      14. Ma, C., Hu, Y., Townsend, J.A., Lagarias, P.I., Marty, M.T., Kolocouris, A.,Wang, J., 2020a. Ebselen, Disulfiram, Carmofur, PX-12, Tideglusib, and Shikonin Are Nonspecific Promiscuous SARS-CoV-2 Main Protease Inhibitors. ACS Pharmacol Transl Sci. 3, 1265-1277.

      15. Ma, C., Sacco, M.D., Hurst, B., Townsend, J.A., Hu, Y., Szeto, T., Zhang, X., Tarbet, B., Marty, M.T., Chen, Y.,Wang, J., 2020b. Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease. Cell Res. 30, 678-692.

      16. Mandal, A., Jha, A.K., Hazra, B., 2021. Plant Products as Inhibitors of Coronavirus 3CL Protease. Front Pharmacol. 12, 583387.

      17. Mccarthy, M.W., 2023. VV116 as a potential treatment for COVID-19. Expert Opin Pharmacother. 24, 675-678.

      18. Newman, D.J., Cragg, G.M., 2016. Natural Products as Sources of New Drugs from 1981 to 2014. J Nat Prod. 79, 629-661.

      19. Olagnier, D., Farahani, E., Thyrsted, J., Blay-Cadanet, J., Herengt, A., Idorn, M., Hait, A., Hernaez, B., Knudsen, A., Iversen, M.B., Schilling, M., Jorgensen, S.E., Thomsen, M., Reinert, L.S., Lappe, M., Hoang, H.D., Gilchrist, V.H., Hansen, A.L., Ottosen, R., Nielsen, C.G., Moller, C., Van Der Horst, D., Peri, S., Balachandran, S., Huang, J., Jakobsen, M., Svenningsen, E.B., Poulsen, T.B., Bartsch, L., Thielke, A.L., Luo, Y., Alain, T., Rehwinkel, J., Alcami, A., Hiscott, J., Mogensen, T.H., Paludan, S.R., Holm, C.K., 2020. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat Commun. 11, 4938.

      20. Owen, D.R., Allerton, C.M.N., Anderson, A.S., Aschenbrenner, L., Avery, M., Berritt, S., Boras, B., Cardin, R.D., Carlo, A., Coffman, K.J., Dantonio, A., Di, L., Eng, H., Ferre, R., Gajiwala, K.S., Gibson, S.A., Greasley, S.E., Hurst, B.L., Kadar, E.P., Kalgutkar, A.S., Lee, J.C., Lee, J., Liu, W., Mason, S.W., Noell, S., Novak, J.J., Obach, R.S., Ogilvie, K., Patel, N.C., Pettersson, M., Rai, D.K., Reese, M.R., Sammons, M.F., Sathish, J.G., Singh, R.S.P., Steppan, C.M., Stewart, A.E., Tuttle, J.B., Updyke, L., Verhoest, P.R., Wei, L., Yang, Q., Zhu, Y., 2021. An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19. Science 374, 1586-1593.

      21. Ratajczak, M.Z., Kucia, M., 2020. SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine "storm" and risk factor for damage of hematopoietic stem cells. Leukemia 34, 1726-1729.

      22. Sacco, M.D., Ma, C., Lagarias, P., Gao, A., Townsend, J.A., Meng, X., Dube, P., Zhang, X., Hu, Y., Kitamura, N., Hurst, B., Tarbet, B., Marty, M.T., Kolocouris, A., Xiang, Y., Chen, Y., Wang, J., 2020. Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against M(pro) and cathepsin L. Sci Adv. 6, eabe0751.

      23. Saravolatz, L.D., Depcinski, S., Sharma, M., 2023. Molnupiravir and Nirmatrelvir-Ritonavir:Oral Coronavirus Disease 2019 Antiviral Drugs. Clin Infect Dis. 76, 165-171.

      24. Shah, A., 2020. Novel Coronavirus-Induced NLRP3 Inflammasome Activation:A Potential Drug Target in the Treatment of COVID-19. Front Immunol. 11, 1021.

      25. Shang, W., Dai, W., Yao, C., Xu, L., Tao, X., Su, H., Li, J., Xie, X., Xu, Y., Hu, M., Xie, D., Jiang, H., Zhang, L., Liu, H., 2022. In vitro and in vivo evaluation of the main protease inhibitor FB2001 against SARS-CoV-2. Antiviral Res. 208, 105450.

      26. Sun, Q., Ye, F., Liang, H., Liu, H., Li, C., Lu, R., Huang, B., Zhao, L., Tan, W., Lai, L., 2021. Bardoxolone and bardoxolone methyl, two Nrf2 activators in clinical trials, inhibit SARS-CoV-2 replication and its 3C-like protease. Signal Transduct Target Ther. 6, 212.

      27. Unoh, Y., Uehara, S., Nakahara, K., Nobori, H., Yamatsu, Y., Yamamoto, S., Maruyama, Y., Taoda, Y., Kasamatsu, K., Suto, T., Kouki, K., Nakahashi, A., Kawashima, S., Sanaki, T., Toba, S., Uemura, K., Mizutare, T., Ando, S., Sasaki, M., Orba, Y., Sawa, H., Sato, A., Sato, T., Kato, T., Tachibana, Y., 2022. Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19. J Med Chem. 65, 6499-6512.

      28. Vuong, W., Khan, M.B., Fischer, C., Arutyunova, E., Lamer, T., Shields, J., Saffran, H.A., Mckay, R.T., Van Belkum, M.J., Joyce, M.A., Young, H.S., Tyrrell, D.L., Vederas, J.C., Lemieux, M.J., 2020. Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication. Nat Commun. 11, 4282.

      29. Wang, M., Cao, R., Zhang, L., Yang, X., Liu, J., Xu, M., Shi, Z., Hu, Z., Zhong, W., Xiao, G., 2020. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 30, 269-271.

      30. Wang, Q., Wu, J., Wang, H., Gao, Y., Liu, Q., Mu, A., Ji, W., Yan, L., Zhu, Y., Zhu, C., Fang, X., Yang, X., Huang, Y., Gao, H., Liu, F., Ge, J., Sun, Q., Yang, X., Xu, W., Liu, Z., Yang, H., Lou, Z., Jiang, B., Guddat, L.W., Gong, P.,Rao, Z., 2020. Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase. Cell 182, 417-428 e413.

      31. Wu, F., Zhao, S., Yu, B., Chen, Y.M., Wang, W., Song, Z.G., Hu, Y., Tao, Z.W., Tian, J.H., Pei, Y.Y., Yuan, M.L., Zhang, Y.L., Dai, F.H., Liu, Y., Wang, Q.M., Zheng, J.J., Xu, L., Holmes, E.C., Zhang, Y.Z., 2020. A new coronavirus associated with human respiratory disease in China. Nature 579, 265-269.

      32. Yang, H., Huang, J., Gao, Y., Wen, Z., Peng, L., Ci, X., 2020. Oridonin attenuates carrageenan-induced pleurisy via activation of the KEAP-1/Nrf2 pathway and inhibition of the TXNIP/NLRP3 and NF-kappaB pathway in mice. Inflammopharmacology 28, 513-523.

      33. Yang, H., Lv, H., Li, H., Ci, X., Peng, L., 2019. Oridonin protects LPS-induced acute lung injury by modulating Nrf2-mediated oxidative stress and Nrf2-independent NLRP3 and NF-kappaB pathways. Cell Commun Signal. 17, 62.

      34. Ye, Y.C., Wang, H.J., Xu, L., Liu, W.W., Liu, B.B., Tashiro, S., Onodera, S., Ikejima, T., 2012. Oridonin induces apoptosis and autophagy in murine fibrosarcoma L929 cells partly via NO-ERK-p53 positive-feedback loop signaling pathway. Acta Pharmacol Sin. 33, 1055-1061.

      35. Zhang, J.L., Li, Y.H., Wang, L.L., Liu, H.Q., Lu, S.Y., Liu, Y., Li, K., Liu, B., Li, S.Y., Shao, F.M., Wang, K., Sheng, N., Li, R., Cui, J.J., Sun, P.C., Ma, C.X., Zhu, B., Wang, Z., Wan, Y.H., Yu, S.S., Che, Y., Wang, C.Y., Wang, C., Zhang, Q., Zhao, L.M., Peng, X.Z., Cheng, Z., Chang, J.B., Jiang, J.D., 2021. Azvudine is a thymus-homing anti-SARS-CoV-2 drug effective in treating COVID-19 patients. Signal Transduct Target Ther. 6, 414.

      36. Zhang, Q.Y., Deng, C.L., Liu, J., Li, J.Q., Zhang, H.Q., Li, N., Zhang, Y.N., Li, X.D., Zhang, B., Xu, Y., Ye, H.Q., 2021. SARS-CoV-2 replicon for high-throughput antiviral screening. J Gen Virol. 102, 001583.

      37. Zhang, Y., Li, C., Ke, X., Luo, D., Liu, Y., Chen, Q., Wang, H., Song, X., Zheng, Z., 2022. Development of a biosensor assessing SARS-CoV-2 main protease proteolytic activity in living cells for antiviral drugs screening. Virol Sin. 37, 459-461.

      38. Zhang, Z.R., Zhang, Y.N., Li, X.D., Zhang, H.Q., Xiao, S.Q., Deng, F., Yuan, Z.M., Ye, H.Q., Zhang, B., 2020. A cell-based large-scale screening of natural compounds for inhibitors of SARS-CoV-2. Signal Transduct Target Ther. 5, 218.

      39. Zhang, Z.R., Zhang, Y.N., Zhang, H.Q., Zhang, Q.Y., Li, N., Li, Q., Deng, C.L., Zhang, B., Li, X.D., Ye, H.Q., 2022. Berbamine hydrochloride potently inhibits SARS-CoV-2 infection by blocking S protein-mediated membrane fusion. PLoS Negl Trop Dis. 16, e0010363.

      40. Zhong, B., Peng, W., Du, S., Chen, B., Feng, Y., Hu, X., Lai, Q., Liu, S., Zhou, Z.W., Fang, P., Wu, Y., Gao, F., Zhou, H.,Sun, L., 2022. Oridonin Inhibits SARS-CoV-2 by Targeting Its 3C-Like Protease. Small Sci, 2, 2100124.

      41. Zhou, P., Yang, X.L., Wang, X.G., Hu, B., Zhang, L., Zhang, W., Si, H.R., Zhu, Y., Li, B., Huang, C.L., Chen, H.D., Chen, J., Luo, Y., Guo, H., Jiang, R.D., Liu, M.Q., Chen, Y., Shen, X.R., Wang, X., Zheng, X.S., Zhao, K., Chen, Q.J., Deng, F., Liu, L.L., Yan, B., Zhan, F.X., Wang, Y.Y., Xiao, G.F.,Shi, Z.L., 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579, 270-273.

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      Oridonin inhibits SARS-CoV-2 replication by targeting viral proteinase and polymerase

        Corresponding author: Bo Zhang, zhangbo@wh.iov.cn
        Corresponding author: Xiaodan Li, lxd@live.cn
        Corresponding author: Bing Zhu, zhubing@gzhmu.edu.cn
        Corresponding author: Hanqing Ye, yehq@wh.iov.cn
      • a. Virus Laboratory, Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China;
      • b. Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China;
      • c. University of Chinese Academy of Sciences, Beijing, 100049, China;
      • d. Hunan Normal University, School of Medicine, Changsha, 410081, China
      • Received Date: 18 December 2022
      • Accepted Date: 27 April 2023

      Abstract: COVID-19 has become a global public health crisis since its outbreak in China in December 2019. Currently there are few clinically effective drugs to combat SARS-CoV-2 infection. The main protein (Mpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 are involved in the viral replication, and might be prospective targets for anti-coronavirus drug development. Here, we investigated the antiviral activity of oridonin, a natural small-molecule compound, against SARS-CoV-2 infection in vitro. The time-of-addition analysis showed that oridonin efficiently inhibited SARS-CoV-2 infection by interfering with the genome replication at the post-entry stage. Mechanistically, the inhibition of viral replication by oridonin depends on the oxidation activity of α, β-unsaturated carbonyl. Further experiments showed that oridonin not only effectively inhibited SARS-CoV-2 Mpro activity, but also had some inhibitory effects on PLpro-mediated deubiquitinating and viral polymerase-catalyzed RNA elongation activities at high concentrations. In particular, oridonin could inhibit the bat SARS-like CoV and the newly emerged SARS-CoV-2 omicron variants (BA.1 and BA.2), which highlights its potential as a pan-coronavirus antiviral agent. Overall, our data provide strong evidence that oridonin is an efficient antiviral agent against SARS-CoV-2 infection.

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