Recently, Prof. Wang Peihui from the Advanced Medical Research Institute of Shandong University, Prof. Wang Jian and Prof. He Fuchu from the National Center for Protein Sciences, Beijing Institute of Lifeomics, and Prof. Wang Jianwei from Chinese Academy of Medical Sciences and Peking Union Medical College collaborated in publishing a research article entitled “An antibody-based proximity labelling map reveals mechanisms of SARS-CoV-2 inhibition of antiviral immunity" in Cell Chemical Biology. The research uses the cutting-edge technology of proteomics and systems biology approach to reveal the mechanism of the SARS-CoV-2 manipulating the antiviral and immune responses.

SARS-CoV-2 which causes COVID-19 has spread globally and has infected more than 200 million people. The interaction between SARS-CoV-2 and human proteins is essential for understanding the basic process of viral infection. Complementary to traditional AP-MS methods, biotin-ligase-based proximity labelling technology is a powerful tool to investigate proximal protein interactions in living cells and organisms. To extend the knowledge of interactions between SARS-CoV-2 and humans, this study systematically investigates the interactome of 29 viral proteins in human cells by using an antibody-based TurboID assay. In total, 1,388 high-confidence human proximal proteins with biotinylated sites are identified. Notably, this study reveals that SARS-CoV-2 manipulates the antiviral and immune responses.

Interferon (IFN) plays a critical role in hosting antiviral defence by inducing hundreds of interferon-stimulated genes (ISGs) through the JAK/STAT pathway. The multiple viral proteins encoded by SARS-CoV-2 inhibit the production of interferon by targeting the key adaptor protein MAVS of the cytoplasmic viral RNA sensing pathway RIG-I/MAVS/TBK1/IRF3. SARS-CoV-2 proteins NSP14 and NSP16 can also inhibit interferon by interfering with the Hippo pathway. In addition, NSP9 targets the methyltransferase SETD2 to block IFN-STAT1 signalling.

ACE2 is the host cell receptor responsible for SARS-CoV-2 entry. This study also found that the membrane protein ITGB1 associates with human ACE2 to mediate SARS-CoV-2 entry. Reducing or blocking ITGB1 can both inhibit the infection efficiency of SARS-CoV-2, thus providing a new target for inhibiting SARS-CoV-2 infection.

To identify the potential targets and already approved drugs for the therapeutic treatment of COVID-19, the proximal proteins of SARS-CoV-2 were assessed using the DrugBank database; 70 proximal proteins targeted by 248 drugs were obtained, among which 101 drugs have already been approved by the Food and Drug Administration (FDA). To verify the role of the drug during SARS-CoV-2 infection, the study randomly selected 12 compounds and tested their efficacy in inhibiting SARS-CoV-2 and found that three of them significantly inhibited the replication of SARS-CoV-2, including azacitidine, thimerosal, and verteporfin. Verteporfin significantly inhibited the replication of SARS-CoV-2 at a very low concentration (half maximal inhibitory concentration [IC50] = 0.07 μM). Taken together, this study sheds light on the basic research into SARS-CoV-2 infection and the development of clinical drugs for COVID-19.

Zhang Yuehui, Shang Limin, Liu Yuchen, Jin Chaozhi and Zhao Yanan from the National Center for Protein Sciences of Beijing Institute of Lifeomics, Zhang Jing from the Advanced Medical Research Institute of Shandong University, and Lei Xiaobo from Chinese Academy of Medical Sciences and Peking Union Medical College are the co-first authors of this paper. Wang Jian, Wang Pei-Hui, He Fuchu and Wang Jianwei are the co-corresponding authors.

Link to this paper:

https://www.sciencedirect.com/science/article/pii/S2451945621004426?dgcid=coauthor