Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

doi:10.1007/s13238-020-00768-w

Protein Cell

2020, Vol. 11

Issue (10) : 723-739 https://doi.org/10.1007/s13238-020-00768-w

RESEARCH ARTICLE

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Rui Xiong², Leike Zhang³, Shiliang Li², Yuan Sun³, Minyi Ding², Yong Wang¹, Yongliang Zhao¹, Yan Wu³, Weijuan Shang³, Xiaming Jiang³, Jiwei Shan², Zihao Shen², Yi Tong², Liuxin Xu², Yu Chen¹, Yingle Liu¹, Gang Zou⁴, Dimitri Lavillete⁴, Zhenjiang Zhao², Rui Wang², Lili Zhu², Gengfu Xiao³, Ke Lan¹, Honglin Li²(

), Ke Xu^1,⁴(

)

¹. State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
². Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
³. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China
⁴. CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China

Download: PDF(5541 KB)
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Abstract

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identiﬁed two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic proﬁles, which all showed broadspectrum antiviral effects against various RNA viruses, including inﬂuenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC₅₀ of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the ﬁrst to validate that DHODH is an attractive host target through high antiviral efﬁcacy invivoand low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leﬂunomide/Teriﬂunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Keywords de novo pyrimidine biosynthesis DHODH inhibitors SARS-CoV-2 inﬂuenza viruses virus replication mmuno-regulation

Corresponding Author(s): Honglin Li,Ke Xu

Online First Date: 22 September 2020 Issue Date: 12 October 2020

Cite this article:

Rui Xiong,Leike Zhang,Shiliang Li, et al. Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2[J]. Protein Cell, 2020, 11(10): 723-739.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-020-00768-w
https://academic.hep.com.cn/pac/EN/Y2020/V11/I10/723

1	A Adalja, T Inglesby (2019) Broad-spectrum antiviral agents: a crucial pandemic tool. Expert Rev Anti Infect Ther 17:467–470 https://doi.org/10.1080/14787210.2019.1635009
2	RS Adcock, YK Chu, JE Golden, DH Chung (2017) Evaluation of anti-Zika virus activities of broad-spectrum antivirals and NIH clinical collection compounds using a cell-based, high-throughput screen assay. Antiviral Res 138:47–56 https://doi.org/10.1016/j.antiviral.2016.11.018
3	T Carroll, M Lo, M Lanteri, J Dutra, K Zarbock, P Silveira, T Rourke, Z-M Ma, L Fritts, S O’Connor (2017) Zika virus preferentially replicates in the female reproductive tract after vaginal inoculation of rhesus macaques. PLoS Pathog 13:e1006537 https://doi.org/10.1371/journal.ppat.1006537
4	SF Chen, FW Perrella, DL Behrens, LM Papp (1992) Inhibition of dihydroorotate dehydrogenase activity by brequinar sodium. Cancer Res 52:3521–3527
5	S Chen, S Ding, Y Yin, L Xu, P Li, MP Peppelenbosch, Q Pan, W Wang (2019) Suppression of pyrimidine biosynthesis by targeting DHODH enzyme robustly inhibits rotavirus replication. Antiviral Res 167:35–44 https://doi.org/10.1016/j.antiviral.2019.04.005
6	L Chen, W Liu, Q Zhang, K Xu, G Ye, W Wu, Z Sun, F Liu, K Wu, B Zhonget al. (2020) RNA based mNGS approach identiﬁes a novel human coronavirus from two individual pneumonia cases in 2019 Wuhan outbreak. Emerg Microbes Infect 9:313–319 https://doi.org/10.1080/22221751.2020.1725399
7	NN Cheung, KK Lai, J Dai, KH Kok, H Chen, K-H Chan, K-Y Yuen, RYT Kao (2017) Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response. J Gen Virol 98:946–954 https://doi.org/10.1099/jgv.0.000758
8	JY Chien, PR Hsueh, WC Cheng, CJ Yu, PC Yang (2006) Temporal changes in cytokine/chemokine proﬁles and pulmonary involvement in severe acute respiratory syndrome. Respirology 11 (6):715–722 https://doi.org/10.1111/j.1440-1843.2006.00942.x
9	D-H Chung, JE Golden, RS Adcock, CE Schroeder, Y-K Chu, JB Sotsky, DE Cramer, PM Chilton, C Song, M Anantpadma (2016) Discovery of a broad-spectrum antiviral compound that inhibits pyrimidine biosynthesis and establishes a type 1 interferonindependent antiviral state. Antimicrob Agents Chemother 60:4552–4562 https://doi.org/10.1128/AAC.00282-16
10	FC Coelho, B Durovni, V Saraceni, C Lemos, CT Codeco, S Camargo, LM De Carvalho, L Bastos, D Arduini, DA Villela (2016) Higher incidence of Zika in adult women than adult men in Rio de Janeiro suggests a signiﬁcant contribution of sexual transmission from men to women. Int J Infect Dis 51:128–132 https://doi.org/10.1016/j.ijid.2016.08.023
11	CP Collaborative (1994) The CCP4 suite: programs for protein crystallography. Acta Crystallogr Sect D 50:760 https://doi.org/10.1107/S0907444994003112
12	P Das, X Deng, L Zhang, MG Roth, BM Fontoura, MA Phillips, JK De Brabander (2013) SAR-based optimization of a 4-quinoline carboxylic acid analogue with potent antiviral activity. ACS Med Chem Lett 4:517–521 https://doi.org/10.1021/ml300464h
13	B Davies, T Morris (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10:1093–1095 https://doi.org/10.1023/A:1018943613122
14	Y Debing, J Neyts, L Delang (2015) The future of antivirals: broadspectrum inhibitors. Curr Opin Infect Dis 28:596–602 https://doi.org/10.1097/QCO.0000000000000212
15	C Deng, S Liu, Q Zhang, M Xu, H Zhang, D Gu, L Shi, J He, G Xiao, B Zhang (2016) Isolation and characterization of Zika virus imported to China using C6/36 mosquito cells. Virol Sin 31:176–179 https://doi.org/10.1007/s12250-016-3778-5
16	YY Diao, WQ Lu, HT Jin, JS Zhu, L Han, MH Xu, R Gao, X Shen, ZJ Zhao, XF Liuet al. (2012) Discovery of diverse human dihydroorotate dehydrogenase inhibitors as immunosuppressive agents by structure-based virtual screening. J Med Chem 55:8341–8349 https://doi.org/10.1021/jm300630p
17	P Emsley, B Lohkamp, WG Scott, K Cowtan (2010) Features and development of Coot. Acta Crystallogr Sect D 66:486–501 https://doi.org/10.1107/S0907444910007493
18	P Evans (2006) Scaling and assessment of data quality. Acta Crystallogr Sect D 62:72–82 https://doi.org/10.1107/S0907444905036693
19	RI Fox, ML Herrmann, CG Frangou, GM Wahl, RE Morris, V Strand, BJ Kirschbaum (1999) Mechanism of action for leﬂunomide in rheumatoid arthritis. Clin Immunol 93:198–208 https://doi.org/10.1006/clim.1999.4777
20	GF Gao (2018) From “A”IV to “Z”IKV: attacks from emerging and reemerging pathogens. Cell 172:1157–1159 https://doi.org/10.1016/j.cell.2018.02.025
21	HN Gao, HZ Lu, B Cao, B Du, H Shang, JH Gan, SH Lu, YD Yang, Q Fang, YZ Shen (2013) Clinical ﬁndings in 111 cases of inﬂuenza A (H7N9) virus infection. N Engl J Med 368:2277–2285 https://doi.org/10.1056/NEJMoa1305584
22	C Grandin, M-L Hourani, YL Janin, D Dauzonne, H Munier-Lehmann, A Paturet, F Taborik, A Vabret, H Contamin, F Tangy (2016) Respiratory syncytial virus infection in macaques is not suppressed by intranasal sprays of pyrimidine biosynthesis inhibitors. Antiviral Res 125:58–62 https://doi.org/10.1016/j.antiviral.2015.11.006
23	Q Han, C Chang, L Li, C Klenk, J Cheng, Y Chen, N Xia, Y Shu, Z Chen, G Gabrielet al. (2014) Sumoylation of inﬂuenza A virus nucleoprotein is essential for intracellular trafﬁcking and virus growth. J Virol 88:9379–9390 https://doi.org/10.1128/JVI.00509-14
24	R Harvey, K Brown, Q Zhang, M Gartland, L Walton, C Talarico, W Lawrence, D Selleseth, N Cofﬁeld, J Learyet al. (2009) GSK983: a novel compound with broad-spectrum antiviral activity. Antiviral Res 82:1–11 https://doi.org/10.1016/j.antiviral.2008.12.015
25	H-H Hoffmann, A Kunz, VA Simon, P Palese, ML Shaw (2011) Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis. Proc Natl Acad Sci 108:5777–5782 https://doi.org/10.1073/pnas.1101143108
26	C Huang, Y Wang, X Li, L Ren, J Zhao, Y Hu, L Zhang, G Fan, J Xu, X Guet al. (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 395:497–506 https://doi.org/10.1016/S0140-6736(20)30183-5
27	I Hung, K To, C Lee, K Lee, W Yan, K Chan, C Ngai, K Law, F Chow, R Liu (2013) Hyperimmune intravenous immunoglobulin treatment: a multicentre double-blind randomized controlled trial for patients with severe A(H1N1)pdm09 infection. Chest 144:464–473 https://doi.org/10.1378/chest.12-2907
28	A Ianevski, PI Andersen, A Merits, M Bjørås, D Kainov (2019) Expanding the activity spectrum of antiviral agents. Drug Discov Today 24:1224–1228 https://doi.org/10.1016/j.drudis.2019.04.006
29	LD Jasenosky, G Neumann, Y Kawaoka (2010) Minigenome-based reporter system suitable for high-throughput screening of compounds able to inhibit ebolavirus replication and/or transcription. Antimicrob Agents Chemother 54:3007 https://doi.org/10.1128/AAC.00138-10
30	PC Jordan, SK Stevens, J Deval (2018) Nucleosides for the treatment of respiratory RNA virus infections. Antiviral Chem Chemother 26:1–19 https://doi.org/10.1177/2040206618764483
31	LP Jordheim, D Durantel, F Zoulim, C Dumontet (2013) Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discov 12:447–464 https://doi.org/10.1038/nrd4010
32	AC Kottkamp, E De Jesus, R Grande, JA Brown, AR Jacobs, JK Lim, KA Stapleford (2019) Atovaquone inhibits arbovirus replication through the depletion of intracellular nucleotides. J Virol 93: e00389–00319 https://doi.org/10.1128/JVI.00389-19
33	S Li, G Luan, X Ren, W Song, L Xu, M Xu, J Zhu, D Dong, Y Diao, X Liuet al. (2015) Rational design of benzylidenehydrazinylsubstituted thiazole derivatives as potent inhibitors of human dihydroorotate dehydrogenase with in vivo anti-arthritic activity. Sci Rep 5:14836 https://doi.org/10.1038/srep14836
34	Z Liu, Z Guo, G Wang, D Zhang, H He, G Li, Y Liu, D Higgins, A Walsh, L Shanahan-Prendergast (2009) Evaluation of the efﬁcacy and safety of a statin/caffeine combination against H5N1, H3N2 and H1N1 virus infection in BALB/c mice. Eur J Pharm Sci 38:215–223 https://doi.org/10.1016/j.ejps.2009.07.004
35	M Lucas-Hourani, D Dauzonne, P Jorda, G Cousin, A Lupan, O Helynck, G Caignard, G Janvier, G André-Leroux, S Khiar (2013) Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity. PLoS Pathog 9:e1003678 https://doi.org/10.1371/journal.ppat.1003678
36	M Lucas-Hourani, D Dauzonne, H Munier-Lehmann, S Khiar, S Nisole, J Dairou, O Helynck, PV Afonso, F Tangy, P-O Vidalain (2017) Original chemical series of pyrimidine biosynthesis inhibitors that boost the antiviral interferon response. Antimicrob Agents Chemother 61:e00383–00317 https://doi.org/10.1128/AAC.00383-17
37	TC Luke, EM Kilbane, JL Jackson, SL Hoffman (2006) Metaanalysis: convalescent blood products for spanish inﬂuenza pneumonia: a future H5N1 Treatment? Ann Intern Med 145:599–609 https://doi.org/10.7326/0003-4819-145-8-200610170-00139
38	P Luthra, J Naidoo, CA Pietzsch, S De, S Khadka, M Anantpadma, CG Williams, MR Edwards, RA Davey, A Bukreyev (2018) Inhibiting pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside pools and activation of innate immune responses. Antiviral Res 158:288–302 https://doi.org/10.1016/j.antiviral.2018.08.012
39	M Marschall, I Niemann, K Kosulin, A Bootz, S Wagner, T Dobner, T Herz, B Kramer, J Leban, D Vitt (2013) Assessment of drug candidates for broad-spectrum antiviral therapy targeting cellular pyrimidine biosynthesis. Antiviral Res 100:640–648 https://doi.org/10.1016/j.antiviral.2013.10.003
40	M Matrosovich, T Matrosovich, W Garten, H-D Klenk (2006) New low-viscosity overlay medium for viral plaque assays. Virol J 3:63 https://doi.org/10.1186/1743-422X-3-63
41	Y Matsuoka, EW Lamirande, K Subbarao (2009) The mouse model for inﬂuenza. Curr Protoc Microbiol 13:15G–3 https://doi.org/10.1002/9780471729259.mc15g03s13
42	IR McNicholl, JJ McNicholl (2001) Neuraminidase inhibitors: zanamivir and oseltamivir. Ann Pharmacother 35:57–70 https://doi.org/10.1345/aph.10118
43	G Mei-jiao, L Shi-fang, C Yan-yan, S Jun-jun, S Yue-feng, R Ting-ting, Z Yong-guang, C Hui-yun (2019) Antiviral effects of selected IMPDH and DHODH inhibitors against foot and mouth disease virus. Biomed Pharmacother 118:109305 https://doi.org/10.1016/j.biopha.2019.109305
44	JY Min, K Subbarao (2010) Cellular targets for inﬂuenza drugs. Nat Biotechnol 28:239–240 https://doi.org/10.1038/nbt0310-239
45	H Munier-Lehmann, PO Vidalain, F Tangy, YL Janin (2013) On dihydroorotate dehydrogenases and their inhibitors and uses. J Med Chem 56:3148–3167 https://doi.org/10.1021/jm301848w
46	GN Murshudov, P Skubák, AA Lebedev, NS Pannu, RA Steiner, RA Nicholls, MD Winn, F Long, AA Vagin (2011) REFMAC5 for the reﬁnement of macromolecular crystal structures. Acta Crystallogr Sect D 67:355–367 https://doi.org/10.1107/S0907444911001314
47	M Qing, G Zou, Q-Y Wang, HY Xu, H Dong, Z Yuan, P-Y Shi (2010) Characterization of dengue virus resistance to brequinar in cell culture. Antimicrob Agents Chemother 54:3686–3695 https://doi.org/10.1128/AAC.00561-10
48	A Raveh, PC Delekta, CJ Dobry, W Peng, PJ Schultz, PK Blakely, AW Tai, T Matainaho, DN Irani, DH Sherman (2013) Discovery of potent broad spectrum antivirals derived from marine actinobacteria. PLoS ONE 8:e82318 https://doi.org/10.1371/journal.pone.0082318
49	B Rozman (2002) Clinical pharmacokinetics of leﬂunomide. Clin Pharmacokinet 41:421–430 https://doi.org/10.2165/00003088-200241060-00003
50	W Song, S Li, Y Tong, J Wang, L Quan, Z Chen, Z Zhao, Y Xu, L Zhu, X Qianet al. (2016) Structure-based design of potent human dihydroorotate dehydrogenase inhibitors as anticancer agents. Med Chem Commun 7:1441–1448 https://doi.org/10.1039/C6MD00179C
51	WW Tang, MP Young, A Mamidi, JA Regla-Nava, K Kim, S Shresta (2016) A mouse model of Zika virus sexual transmission and vaginal viral replication. Cell Rep 17:3091–3098 https://doi.org/10.1016/j.celrep.2016.11.070
52	L Van Hoecke, ER Job, X Saelens, K Roose (2017) Bronchoalveolar lavage of murine lungs to analyze inﬂammatory cell inﬁltration. JoVE 123:e55398 https://doi.org/10.3791/55398
53	S Wan, Q Yi, S Fan, J Lv, X Zhang, L Guo, C Lang, Q Xiao, K Xiao, Z Yiet al. (2020) Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP). medRxiv https://doi.org/10.1101/2020.02.10.20021832
54	CH Wang, C-Y Liu, Y-L Wan, C-L Chou, K-H Huang, H-C Lin, S-M Lin, T-Y Lin, KF Chung, H-P Kuo (2005) Persistence of lung inﬂammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS. Respir Res 6:42 https://doi.org/10.1186/1465-9921-6-42
55	QY Wang, S Bushell, M Qing, HY Xu, A Bonavia, S Nunes, J Zhou, MK Poh, P Florez de Sessions, P Niyomrattanakitet al. (2011) Inhibition of dengue virus through suppression of host pyrimidine biosynthesis. J Virol 85:6548–6556 https://doi.org/10.1128/JVI.02510-10
56	M Wang, R Cao, L Zhang, X Yang, J Liu, M Xu, Z Shi, Z Hu, W Zhong, G Xiao (2020) Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 30:269–271 https://doi.org/10.1038/s41422-020-0282-0
57	CK Wong, CWK Lam, AKL Wu, WK Ip, NLS Lee, IHS Chan, JJY Sung (2004) Plasma inﬂammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 136:95–103 https://doi.org/10.1111/j.1365-2249.2004.02415.x
58	F Wu, S Zhao, B Yu, YM Chen, W Wang, ZG Song, Y Hu, ZW Tao, JH Tian, YY Peiet al. (2020) A new coronavirus associated with human respiratory disease in China. Nature 579:265–269 https://doi.org/10.1038/s41586-020-2008-3
59	Y Yang, L Cao, H Gao, Y Wu, Y Wang, F Fang, T Lan, Z Lou, Y Rao (2019) Discovery, optimization, and target identiﬁcation of novel potent broad-spectrum antiviral inhibitors. J Med Chem 62:4056–4073 https://doi.org/10.1021/acs.jmedchem.9b00091
60	S Yokota (2003) Inﬂuenza-associated encephalopathy–pathophysiology and disease mechanisms. Jpn J Clin Med 61:1953–1958
61	KY Yuen, SS Wong (2005) Human infection by avian inﬂuenza A H5N1. Hong Kong Med J 11:189–199
62	H Zeng, WJ Waldman, DP Yin, DA Knight, J Shen, L Ma, GT Meister, AS Chong, JW Williams (2005) Mechanistic study of malononitrileamide FK778 in cardiac transplantation and CMV infection in rats. Transplantation 79:17–22 https://doi.org/10.1097/01.TP.0000137334.46155.94
63	Y Zhang, J Li, Y Zhan, L Wu, X Yu, W Zhang, L Ye, S Xu, R Sun, Y Wang (2004) Analysis of serum cytokines in patients with severe acute respiratory syndrome. Infect Immun 72:4410–4415 https://doi.org/10.1128/IAI.72.8.4410-4415.2004
64	P Zhou, XL Yang, XG Wang, B Hu, L Zhang, W Zhang, HR Si, Y Zhu, B Li, CL Huanget al. (2020) A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579:270–273 https://doi.org/10.1038/s41586-020-2012-7
65	J Zhu, L Han, Y Diao, X Ren, M Xu, L Xu, S Li, Q Li, D Dong, J Huanget al. (2015a) Design, synthesis, X-ray crystallographic analysis, and biological evaluation of thiazole derivatives as potent and selective inhibitors of human dihydroorotate dehydrogenase. J Med Chem 58:1123–1139 https://doi.org/10.1021/jm501127s
66	JD Zhu, W Meng, XJ Wang, HC Wang (2015b) Broad-spectrum antiviral agents. Front Microbiol 6:517 https://doi.org/10.3389/fmicb.2015.00517

[1]	PAC-0723-20925-LHL_suppl_1	Download
[2]	PAC-0723-20925-LHL_suppl_2	Download

[1]	Zezhong Liu, Wei Xu, Zhenguo Chen, Wangjun Fu, Wuqiang Zhan, Yidan Gao, Jie Zhou, Yunjiao Zhou, Jianbo Wu, Qian Wang, Xiang Zhang, Aihua Hao, Wei Wu, Qianqian Zhang, Yaming Li, Kaiyue Fan, Ruihong Chen, Qiaochu Jiang, Christian T. Mayer, Till Schoofs, Youhua Xie, Shibo Jiang, Yumei Wen, Zhenghong Yuan, Kang Wang, Lu Lu, Lei Sun, Qiao Wang. An ultrapotent pan-β-coronavirus lineage B (β-CoV-B) neutralizing antibody locks the receptor-binding domain in closed conformation by targeting its conserved epitope[J]. Protein Cell, 2022, 13(9): 655-675.
[2]	Yichen Li, Shuaiyao Lu, Jinge Gu, Wencheng Xia, Shengnan Zhang, Shenqing Zhang, Yan Wang, Chong Zhang, Yunpeng Sun, Jian Lei, Cong Liu, Zhaoming Su, Juntao Yang, Xiaozhong Peng, Dan Li. SARS-CoV-2 impairs the disassembly of stress granules and promotes ALS-associated amyloid aggregation[J]. Protein Cell, 2022, 13(8): 602-614.
[3]	Rongjuan Pei, Jianqi Feng, Yecheng Zhang, Hao Sun, Lian Li, Xuejie Yang, Jiangping He, Shuqi Xiao, Jin Xiong, Ying Lin, Kun Wen, Hongwei Zhou, Jiekai Chen, Zhili Rong, Xinwen Chen. Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection[J]. Protein Cell, 2021, 12(9): 717-733.
[4]	Yao Zhao, Xiaoyu Du, Yinkai Duan, Xiaoyan Pan, Yifang Sun, Tian You, Lin Han, Zhenming Jin, Weijuan Shang, Jing Yu, Hangtian Guo, Qianying Liu, Yan Wu, Chao Peng, Jun Wang, Chenghao Zhu, Xiuna Yang, Kailin Yang, Ying Lei, Luke W. Guddat, Wenqing Xu, Gengfu Xiao, Lei Sun, Leike Zhang, Zihe Rao, Haitao Yang. High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors[J]. Protein Cell, 2021, 12(11): 877-888.
[5]	Hua Qin, Andong Zhao. Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics[J]. Protein Cell, 2020, 11(10): 707-722.

Viewed

Full text

Abstract

Cited

Shared

Discussed