Abstract
The new SARS-CoV-2 variant of concern “Omicron” was recently spotted in South Africa and spread quickly around the world due to its enhanced transmissibility. The variant became conspicuous as it harbors more than 30 mutations in the Spike protein with 15 mutations in the receptor-binding domain (RBD) alone, potentially dampening the potency of therapeutic antibodies and enhancing the ACE2 binding. More worrying, Omicron infections have been reported in vaccinees in South Africa and Hong Kong, and that post-vaccination sera poorly neutralize the new variant. Here, we investigated the binding strength of Omicron with ACE2 and monoclonal antibodies that are either approved by the FDA for COVID-19 therapy or undergoing phase III clinical trials. Computational mutagenesis and free energy perturbation could confirm that Omicron RBD binds ACE2 ~2.5 times stronger than prototype SARS-CoV-2. Notably, three substitutions, i.e., T478K, Q493K, and Q498R, significantly contribute to the binding energies and almost doubled the electrostatic potential (ELE) of the RBDOmic–ACE2 complex. Omicron also harbors E484A substitution instead of the E484K that helped neutralization escape of Beta, Gamma, and Mu variants. Together, T478K, Q493K, Q498R, and E484A substitutions contribute to a significant drop in the ELE between RBDOmic–mAbs, particularly in etesevimab, bamlanivimab, and CT-p59. AZD1061 showed a slight drop in ELE and sotrovimab that binds a conserved epitope on the RBD; therefore, it could be used as a cocktail therapy in Omicron-driven COVID-19. In conclusion, we suggest that the Spike mutations prudently devised by the virus facilitate the receptor binding, weakening the mAbs binding to escape the immune response.
Highlights
Since its emergence, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been found to continuously evolve and raise new variants of concerns (VOCs) to avoid host hostilities, i.e., evade the host immune response, increase transmission, and aggress the pathogenesis of coronavirus disease 2019 (COVID-19)
According to the unrooted phylogenic analysis using the global ~4,000 full-genome SARS-CoV-2 sequences from the Global Initiative on Sharing All Influenza Data (GISAID), Omicron stands distant from other VOCs (Figure 1A)
The retained Omicron neutralization in pseudovirus assay [17] may indicate that the salt bridges between the CDRH3 and receptor-binding domain (RBD) may override the clash between RBDOmic D339 and Y100 in CDRH3 that could potently destabilize the RBDOmic– sotrovimab interaction (Supplementary Figure 2D). These results suggest that mutations in the Omicron Spike are precisely designed by the virus, facilitating receptor binding but hindering antibody binding simultaneously and that antibodies recognizing conserved epitope on the Spike of SARS-CoV-2 variants could be used as pan-variant therapeutics
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been found to continuously evolve and raise new variants of concerns (VOCs) to avoid host hostilities, i.e., evade the host immune response, increase transmission, and aggress the pathogenesis of coronavirus disease 2019 (COVID-19). This host adaptation by the virus has been demonstrated by Receptor Binding and Immune Escape of the Omicron the rise of VOCs, including Alpha, Beta, Gamma, and Delta variants that weaken the neutralizing efficacy of antibodies [1,2,3,4]. Since N protein is highly immunogenic [8, 9], these mutations could help escape the host immune response
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