On the 24 th November 2021 the sequence of a new SARS CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titres of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic as well as Alpha, Beta, Gamma, Delta are substantially reduced or fail to neutralize. Titres against Omicron are boosted by third vaccine doses and are high in cases both vaccinated and infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of a large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses, combining mutations conferring tight binding to ACE2 to unleash evolution driven by immune escape, leading to a large number of mutations in the ACE2 binding site which rebalance receptor affinity to that of early pandemic viruses.

Many SARS-CoV-2 variants with naturally acquired mutations have emerged. These mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has been investigated, sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains largely unexplored. Here, we demonstrate that two recently emerging mutations in the receptor-binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429 and B.1.617) and Y453F (in B.1.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce affinity toward the host entry receptor ACE2. Notably, the L452R mutation increases spike stability, viral infectivity, viral fusogenicity, and thereby promotes viral replication. These data suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes and that a further threat of the SARS-CoV-2 pandemic is escape from cellular immunity.

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Humans can be infected by SARS-CoV-2 either through inhalation of airborne viral particles or by touching contaminated surfaces. Structural and functional studies have shown that a single RBD of the SARS-CoV-2 homotrimer spike glycoprotein interacts with ACE2, which serves as its receptor 1,2 . Binding of spike (S) protein to ACE2 and subsequent cleavage by the host protease transmembrane serine protease 2 (TMPRSS2) results in cell and virus membrane fusion and cell entry 1 . Blocking of the ACE2 receptor by specific antibodies prevents viral entry 1,3-5 . In vitro binding measurements have shown that SARS-CoV-2 S protein binds ACE2 with an affinity of around 10 nM, which is about tenfold tighter than the binding of the SARS-CoV S protein 2,4,6 . It has been suggested that this is, at least partially, responsible for the higher infectivity of SARS-CoV-2 7 . Recently, three major SARS-CoV2 variants of concern have emerged and mutations in the RBD of the spike proteins of these variants have further strengthened this hypothesis. Deep-mutational scanning of the RBD domain showed that the N501Y mutation in the Alpha variant to enhances binding to ACE2 7 . The Beta variant has three altered residues in the ACE2-binding site (K417N, E484K and N501Y), and has spread extremely rapidly, becoming the dominant lineage in the Eastern Cape and Western Cape Provinces within weeks 8 . The Gamma variant, with independent K417T, E484K and N501Y mutations, similar to the B.1.351 variant is spreading rapidly from the Amazon region 9 . Another S mutation associated with increased SARS-CoV-2 infectivity is S477N, which became dominant in many regions 10 .Efficacious vaccines are now being administered 11 . However, especially when a large fraction of the global population remains unvaccinated, the potential of the continuously mutating virus to become at least partially resistant to vaccines means that drug development must continue. Potential therapeutic targets that block viral entry include molecules that block the spike protein, the TMPRSS2 protease or the ACE2 receptor 12 . Multiple high-affinity neutralizing antibodies have been developed 13 . Soluble forms of the ACE2 protein 14,15 or engineered parts or mimics have also shown efficacy 16,17 . In addition, previously developed TMPRSS2 inhibitors have been repurposed for treatment of COVID-19 1 .The development of molecules to block the ACE2 protein has not received much attention. One potential caveat with this approach is the importance of ACE2 biological activity, both as a carboxypeptidase removing a single C-terminal amino acid from angiotensin II to generate angiotensin-(1-7) and in the regulation of amino acid transport and pancreatic insulin secretion 18,19 . Dalbavancin is a drug that blocks the spike protein-ACE2 interaction, however it does so with low affinity 20 (approximately 130 nM).We hypothesized that the RBD domain of SARS-CoV-2 could be used as a competitive inhibitor of the ACE2 receptor binding site. However, this would probably require an RBD with picomola...

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