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In vitro and in vivo evaluation of the main protease inhibitor FB2001 against SARS-CoV-2

文献类型：期刊论文

作者Shang, Weijuan1; Dai, Wenhao2; Yao, Cheng3; Xu, Ling4; Tao, Xiangming5; Su, Haixia2; Li, Jian2; Xie, Xiong2; Xu, Yechun2; Hu, Min3
刊名ANTIVIRAL RESEARCH
出版日期2022-12-01
卷号208页码:10
关键词SARS-CoV-2 SARS-CoV-2 variants FB2001 Main protease PBPK Anti-SARS-CoV-2 in vivo
ISSN号0166-3542
DOI10.1016/j.antiviral.2022.105450
通讯作者Zhang, Leike(zhangleike@wh.iov.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要FB2001 is a drug candidate that targets the main protease of SARS-CoV-2 via covalently binding to cysteine 145. In this study, we evaluated the inhibitory activities of FB2001 against several SARS-CoV-2 variants in vitro and in vivo (in mice), and we also evaluated the histopathological analysis and immunostaining of FB2001 on lung and brain which have been rarely reported. The results showed that FB2001 exhibited potent antiviral efficacy against several current SARS-CoV-2 variants in Vero E6 cells, namely, B.1.1.7 (Alpha): EC50 = 0.39 +/- 0.01 mu M, EC90 = 0.75 +/- 0.01 mu M; B.1.351 (Beta): EC50 = 0.28 +/- 0.11 mu M, EC90 = 0.57 +/- 0.21 mu M; B.1.617.2 (Delta): EC50 = 0.27 +/- 0.05 mu M, EC90 = 0.81 +/- 0.20 mu M; B.1.1.529 (Omicron): EC50 = 0.26 +/- 0.06 mu M and EC50 = 0.042 +/- 0.007 mu M (in the presence of a P-glycoprotein inhibitor). FB2001 remained potent against SARS-CoV-2 repli-cation in the presence of high concentrations of human serum, which indicating that human serum had no significant effect on the in vitro inhibitory activity. Additionally, this inhibitor exhibited an additive effect against SARS-CoV-2 when combined with Remdesivir. Furthermore, FB2001 significantly reduced the SARS-CoV-2 copy numbers and titers in the lungs and brains in vivo, and alleviated the pathological symptoms. In addition, FB2001 could alleviated local bleeding, erythrocyte overflow, edema, and inflammatory cell infiltration in brain tissue, and inhibitors reducing viral titers and improving inflammation in the brain have been rarely reported. A physiologically based pharmacokinetic model was established and verified to predict the FB2001 concentration in human lungs. When FB2001 was administered at 200 mg twice a day for 5 days, the observed Ctrough ss in plasma and predicted Ctrough ss of lung total concentration were 0.163 and 2.5 mu g/mL, which were approximately 9 and 132-fold higher than the EC50 of 0.019 mu g/mL (0.042 mu M) against Omicron variant. Taken together, our study suggests that FB2001 is a promising therapeutic agent in COVID-19 treatment and can be combined with remdesivir to achieve improved clinical outcomes. Owing to its good safety and tolerability in healthy human (NCT05197179 and NCT04766931), FB2001 has been approved for Phase II/III clinical trial (NCT05445934).
资助项目National Natural Science Foundation of China[82130105] ; National Natural Science Foundation of China[82173654] ; National Natural Science Foundation of China[22107107] ; National Key R&D Program of China[2021YFC0864900] ; National Key R&D Program of China[2022YFC0868900] ; Lingang Laboratory[LG202103-03-03] ; Lingang Laboratory[LG202103-04-03] ; China Postdoctoral Science Foundation[BX2021334]
WOS研究方向Pharmacology & Pharmacy ; Virology
语种英语
WOS记录号WOS:000884684500005
出版者ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/304695]  
专题新药研究国家重点实验室
通讯作者Zhang, Leike; Liu, Hong
作者单位1.Chinese Acad Sci, Wuhan Inst Virol, Ctr Biosafety Mega Sci, State Key Lab Virol, Wuhan 430071, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Frontier Biotechnol Inc, Nanjing 211122, Jiangsu, Peoples R China
4.Shanghai Univ Tradit Chinese Med, Shanghai 201203, Peoples R China
5.Beijing BioVoice Technol Co Ltd, Beijing 100068, Peoples R China
6.Lingang Lab, Shanghai 200031, Peoples R China
推荐引用方式
GB/T 7714		 Shang, Weijuan,Dai, Wenhao,Yao, Cheng,et al. In vitro and in vivo evaluation of the main protease inhibitor FB2001 against SARS-CoV-2[J]. ANTIVIRAL RESEARCH,2022,208:10.
APA Shang, Weijuan.,Dai, Wenhao.,Yao, Cheng.,Xu, Ling.,Tao, Xiangming.,...&Liu, Hong.(2022).In vitro and in vivo evaluation of the main protease inhibitor FB2001 against SARS-CoV-2.ANTIVIRAL RESEARCH,208,10.
MLA Shang, Weijuan,et al."In vitro and in vivo evaluation of the main protease inhibitor FB2001 against SARS-CoV-2".ANTIVIRAL RESEARCH 208(2022):10.

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来源：上海药物研究所

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