Infectious diseases caused by viruses, especially the COVID-19 pandemic, have brought heavy disasters to human society. Although antibodies, vaccines and small-molecule drugs have been widely developed and used in epidemic prevention and control, the rapid mutation of the virus has resulted in the failure of many antibodies and breakthrough infection of vaccines. Therefore, broad-spectrum antiviral agents are urgently needed.
Many viruses, including HIV, COVID-19, influenza A, Lassa fever and Ebola, have dense glycan shields on the surface of their proteins, also known as sugar shields. The main reason why these viruses evade the host's immune surveillance is shielding high-immunogenicity epitopes by the sugar shield. During rapid proliferation, many viral sugar proteins skip the complex glycosylation modifications in the Golgi apparatus during processing, leaving plentiful less complex high mannose glycans in the sugar shield. As such, the conserved structural feature of the viral sugar shield (abundant high mannose) can be a potential target for broad-spectrum inhibition against constantly mutating viruses. However, glycans have very similar structures, and their specific recognition presents great challenges.
In order to apply the biomimetic molecular recognition technology accumulated by his research group for many years to the major social needs of COVID-19, Professor Zhen Liu quickly mobilized and organized a team at the early stage of the outbreak, conducted in-depth investigations, actively tackled key problems, and fully cooperated with the leading antiviral research teams outside the university to develop innovative broad-spectrum and efficient antiviral agents. The team first developed aptamers capable of binding high mannose, and on this basis developed dendritic aptamers and tetrahedral nanostructures with polyvalent high mannose binding capability, which showed certain broad-spectrum virus inhibition against pseudovirus of the novel coronavirus (SARS-CoV-2) (CCS Chem. 2022, DOI: 10.31635/ccschem. 022.202101747). In addition, the team developed a DNA nanocrown that matches the topology of the surface spike protein of the novel coronavirus, achieving efficient suppression of both the wild strain of SARS-CoV-2 and several important variants (CCS Chem. 2022, DOI: 10.31635/ ccschem.022.202201945). Particularly, by using the advanced molecular imprinting technology developed by this team (Angew. Chem. In. Ed. 2015, 54, 10211-10215; Nat. Protoc. 2017, 12, 964-987; Adv. Sci. 2021, 8, 2101713), after overcoming a series of challenges such as the difficulties in the synthesis of imprinting template, the team developed a nanostructured artificial antibody (nanoscale molecularly-imprinted polymer, nanoMIP) capable of hypervalently binding high mannose. By targeting the sugar shield of the viruses, the nano-artificial antibody could not only block virus-receptor interactions, but also induce viral aggregation and promote phagocytosis and clearance of macrophages. The nano-artificial antibody exhibited potent and broad-spectrum inhibition against viruses with high mannose, including HIV, Lassa fever virus, and SARS-CoV-2 and its major variants (such as Delta and Omicron). The sugar shield-targeting nano-artificial antibody provides a new strategy and technical path for the further development of broad-spectrum antiviral therapeutics and novel vaccine adjuvants.
Figure 1. Schematic of virus inhibition by anti-high mannose nanoMIP.
This study was recently published online in the journal Advanced Science. Professor Zhen Liu and Professor Cheng-Feng Qin at the Academy of Military Medical Sciences are co-corresponding authors of the paper. Ying Li (PhD student) and Dr. Shuxin Xu (Associate researcher) at Nanjing University, as well as Dr. Qing Ye and Dr. Hang Chi at the Academy of Military Medical Sciences are co-first authors of the paper. Dr. Qin Cheng-Feng and his team and Dr. Li Bin and his team at Jiangsu Academy of Agricultural Sciences provided important technical support. This research was supported by the Key Research and Development Project of the Ministry of Science and Technology, the key project of the National Natural Science Foundation of China and the Excellence Program of Nanjing University.
Related information:
Ying Li, Shuxin Xu, Qing Ye, Hang Chi, Zhanchen Guo, Jingran Chen, Mei Wu, Baochao Fan, Bin Li, Cheng-Feng Qin*, Zhen Liu*. Rational Development of Hypervalent Glycan Shield-Binding Nanoparticles with Broad-Spectrum Inhibition against Fatal Viruses Including SARS-CoV-2 Variants. Advanced Science, 2022, 2202689.
https://onlinelibrary.wiley.com/doi/10.1002/advs.202202689