Omicron: A Heavily Mutated SARS-CoV-2 Variant Exhibits Stronger Binding to ACE2 and Potently Escapes Approved COVID-19 Therapeutic Antibodies

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.

Automated summary

The new SARS-CoV-2 variant Omicron has enhanced transmissibility and multiple mutations that may weaken the effectiveness of therapeutic antibodies. Computational studies have shown that Omicron binds to ACE2 with a higher strength and specific mutations contribute significantly to the binding energies. These mutations also result in a drop in the electrostatic potential between RBDOmic and monoclonal antibodies, particularly etesevimab, bamlanivimab, and CT-p59. Sotrovimab, which targets a conserved epitope on the Spike protein, could be used as a cocktail therapy for Omicron-driven COVID-19.