ABSTRACT
The global pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in widespread social and economic disruption. Effective interventions are urgently needed for the prevention and treatment of COVID-19. Neutralizing monoclonal antibodies (mAbs) have demonstrated their prophylactic and therapeutic efficacy against SARS-CoV-2, and several have been granted authorization for emergency use. Here, we discover and characterize a fully human cross-reactive mAb, MW06, which binds to both SARS-CoV-2 and SARS-CoV spike receptor-binding domain (RBD) and disrupts their interaction with angiotensin-converting enzyme 2 (ACE2) receptors. Potential neutralization activity of MW06 was observed against both SARS-CoV-2 and SARS-CoV in different assays. The complex structure determination and epitope alignment of SARS-CoV-2 RBD/MW06 revealed that the epitope recognized by MW06 is highly conserved among SARS-related coronavirus strains, indicating the potential broad neutralization activity of MW06. In in vitro assays, no antibody-dependent enhancement (ADE) of SARS-CoV-2 infection was observed for MW06. In addition, MW06 recognizes a different epitope from MW05, which shows high neutralization activity and has been in a Phase 2 clinical trial, supporting the development of the cocktail of MW05 and MW06 to prevent against future escaping variants. MW06 alone and the cocktail show good effects in preventing escape mutations, including a series of variants of concern, B.1.1.7, P.1, B.1.351, and B.1.617.1. These findings suggest that MW06 recognizes a conserved epitope on SARS-CoV-2, which provides insights for the development of a universal antibody-based therapy against SARS-related coronavirus and emerging variant strains, and may be an effective anti-SARS-CoV-2 agent.
Subject(s)
Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , SARS-CoV-2/immunology , Severe acute respiratory syndrome-related coronavirus/immunology , Amino Acid Sequence , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/chemistry , Antibodies, Viral/therapeutic use , Antibody-Dependent Enhancement , COVID-19/therapy , Conserved Sequence , Cross Reactions , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , Humans , Models, Molecular , Neutralization Tests , Pandemics , Protein Domains , Protein Interaction Domains and Motifs , Severe acute respiratory syndrome-related coronavirus/chemistry , Severe acute respiratory syndrome-related coronavirus/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , COVID-19 Drug TreatmentABSTRACT
AIM AND OBJECTIVE: Maxingyigan (MXYG) decoction is a traditional Chinese medicine (TCM) prescription. However, how MXYG acts against coronavirus disease 2019 (COVID-19) is not known. We investigated the active ingredients and the therapeutic targets of MXYG decoction against COVID-19. METHODS: A network pharmacology strategy involving drug-likeness evaluation, prediction of oral bioavailability, network analyses, and virtual molecular docking was used to predict the mechanism of action of MXYG against COVID-19. RESULTS: Thirty-three core COVID-19-related targets were identified from 1023 gene targets through analyses of protein-protein interactions. Eighty-six active ingredients of MXYG decoction hit by 19 therapeutic targets were screened out by analyses of a compound-compound target network. Via network topology, three "hub" gene targets (interleukin (IL-6), caspase-3, IL-4) and three key components (quercetin, formononetin, luteolin) were recognized and verified by molecular docking. Compared with control compounds (ribavirin, arbidol), the docking score of quercetin to the IL-6 receptor was highest, with a score of 5. Furthermore, the scores of three key components to SARS-CoV-2 are large as 4, 5, and 5, respectively, which are even better than those of ribavirin at 3. Bioinformatics analyses revealed that MXYG could prevent and treat COVID-19 through anti-inflammatory and immunity-based actions involving activation of T cells, lymphocytes, and leukocytes, as well as cytokine-cytokine-receptor interaction, and chemokine signaling pathways. CONCLUSION: The hub genes of COVID-19 helped to reveal the underlying pathogenesis and therapeutic targets of COVID-19. This study represents the first report on the molecular mechanism of MXYG decoction against COVID-19.