ProtoporphyrinⅨand verteporfin potently inhibit SARS-CoV-2 infection in vitro and in a mouse model expressing human ACE2  

原卟啉Ⅸ和维替泊芬在细胞水平和小鼠体内有效抑制新型冠状病毒的感染

作　　者：Chenjian Gu Yang Wu Huimin Guo Yuanfei Zhu Wei Xu Yuyan Wang Yu Zhou Zhiping Sun Xia Cai Yutang Li Jing Liu Zhong Huang Zhenghong Yuan Rong Zhang Qiang Deng Di Qu Youhua Xie 谷陈建;吴旸;郭慧敏;朱园飞;徐巍;王玉燕;周瑜;孙志平;蔡霞;李玉瑭;刘晶;黄忠;袁正宏;张荣;邓强;瞿涤;谢幼华(Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS),Department of Medical Microbiology and Parasitology,School of Basic Medical Sciences,Shanghai Institute of Infectious Diseases and Biosecurity,Shanghai Medical College,Fudan University,Shanghai 200032,China;BSL-3 Laboratory of Fudan University,School of Basic Medical Sciences,Shanghai Medical College,Fudan University,Shanghai 200032,China;CAS Key Laboratory of Molecular Virology&Immunology,Institut Pasteur of Shanghai,Chinese Academy of Sciences,University of Chinese Academy of Sciences CAS Key Laboratory of Molecular Virology&Immunology,Institut Pasteur of Shanghai,Chinese Academy of Sciences,University of Chinese Academy of Sciences,Shanghai 200031,China;Children’s Hospital,Shanghai Medical College,Fudan University,Shanghai 201102,China)

机构地区：[1]Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS),Department of Medical Microbiology and Parasitology,School of Basic Medical Sciences,Shanghai Institute of Infectious Diseases and Biosecurity,Shanghai Medical College,Fudan University,Shanghai 200032,China [2]BSL-3 Laboratory of Fudan University,School of Basic Medical Sciences,Shanghai Medical College,Fudan University,Shanghai 200032,China [3]CAS Key Laboratory of Molecular Virology&Immunology,Institut Pasteur of Shanghai,Chinese Academy of Sciences,University of Chinese Academy of Sciences CAS Key Laboratory of Molecular Virology&Immunology,Institut Pasteur of Shanghai,Chinese Academy of Sciences,University of Chinese Academy of Sciences,Shanghai 200031,China [4]Children’s Hospital,Shanghai Medical College,Fudan University,Shanghai 201102,China

出　　处：《Science Bulletin》2021年第9期925-936,M0004,共13页科学通报（英文版）

基　　金：supported by the National Science and Technology Major Project(NSTMP)for the Prevention and Treatment of Infectious Diseases(2018ZX10734401,2018ZX10301208);the NSTMP for the Development of Novel Drugs(2019ZX09721001);the Project of Novel Coronavirus Research of Fudan University,China Postdoctoral Science Foundation(2020T130016ZX)。

摘　　要：The SARS-CoV-2 infection is spreading rapidly worldwide.Efficacious antiviral therapeutics against SARSCo V-2 is urgently needed.Here,we discovered that protoporphyrin IX(Pp IX)and verteporfin,two Food and Drug Administration(FDA)-approved drugs,completely inhibited the cytopathic effect produced by SARS-CoV-2 infection at 1.25 lmol/L and 0.31 lmol/L,respectively,and their EC50 values of reduction of viral RNA were at nanomolar concentrations.The selectivity indices of Pp IX and verteporfin were 952.74 and 368.93,respectively,suggesting a broad margin of safety.Importantly,Pp IX and verteporfin prevented SARS-CoV-2 infection in mice adenovirally transduced with human angiotensin-converting enzyme 2(ACE2).The compounds,sharing a porphyrin ring structure,were shown to bind viral receptor ACE2 and interfere with the interaction between ACE2 and the receptor-binding domain of viral S protein.Our study suggests that Pp IX and verteporfin are potent antiviral agents against SARS-CoV-2 infection and sheds new light on developing novel chemoprophylaxis and chemotherapy against SARS-CoV-2.新型冠状病毒(新冠病毒)引起的疫情当前仍在全球蔓延,因而研究有效的新冠病毒疫苗和抗病毒药物成为当务之急.本研究发现原卟啉Ⅸ(ProtoporphyrinⅨ)和维替泊芬(Verteporfin)这两种FDA批准的药物分别在1.25和0.31μmolL-1的浓度下,能在Vero E6细胞上完全抑制新冠病毒的感染,并阻止新冠病毒感染造成的细胞病变.同时,原卟啉IX和维替泊芬的选择性指数(Selectivity indices,SI)分别为952.74和368.93,表明其具有很广的安全用药范围.进一步利用表达人源ACE2(hACE2)的腺病毒(Ad5-h ACE2)建立新冠病毒小鼠感染模型后,发现原卟啉IX和维替泊芬可以完全阻断小鼠感染新冠病毒.通过药物–蛋白分子对接模拟、药物-蛋白互作实验,发现原卟啉IX和维替泊芬这两个具有卟啉环结构的化合物能够直接结合新冠病毒受体——ACE2,并干扰病毒S蛋白与受体ACE2之间的相互作用.本研究表明,原卟啉IX和维替泊芬在细胞水平和动物水平均能有效抗新冠病毒感染,为开发新型抗新冠病毒药物提供了新的思路.

关 键 词：SARS-CoV-2 ACE2 ProtoporphyrinⅨ VERTEPORFIN 

分 类 号：R563.1[医药卫生—呼吸系统]