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Mutations in the SARS-CoV-2 spike proteins affected the ACE2-binding affinity during the development of Omicron

Kouichi Tachibana1, Yoshihiko Nakamura2, Thi Ly Do3

  • 1Tokai University School of Medicine, Department of Internal Medicine, Division of Hematology and Oncology, 143 Shimokasuya, Isehara, Kanagawa, Japan.

Biochemical and Biophysical Research Communications
|May 17, 2024
PubMed

Insights

SARS-CoV-2 mutations drive pandemics. Early Omicron variants had lower ACE2 binding, while later ones increased it, suggesting a role in Omicron evolution. Alpha and Omicron strains bound mouse ACE2, hinting at a mouse origin for Omicron.

Area of Science:

  • Virology
  • Molecular Biology
  • Evolutionary Biology

Background:

  • Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mutations have led to successive pandemic waves.
  • Understanding the functional impact of these mutations, particularly on the spike (S) protein and its interaction with the Angiotensin-Converting Enzyme 2 (ACE2) receptor, is crucial.

Purpose of the Study:

  • To investigate the binding affinity of SARS-CoV-2 S protein variants with human and mouse ACE2.
  • To elucidate the role of ACE2-binding affinity in the evolutionary trajectory of SARS-CoV-2 variants, including the Omicron lineage.

Main Methods:

  • Comparative analysis of binding affinities between different SARS-CoV-2 S protein variants (prototype, Alpha, Omicron BA.1, BA.5, XBB.1.5) and human ACE2.
  • Assessment of binding interactions with mouse ACE2 for key SARS-CoV-2 variants.

Main Results:

  • Omicron BA.1 exhibited significantly lower binding affinity to human ACE2 compared to prototype SARS-CoV-2 and the Alpha strain.
  • Later Omicron variants (BA.5, XBB.1.5) demonstrated significantly higher ACE2-binding affinity than Omicron BA.1.
  • Alpha and Omicron variants, unlike the prototype strain, bound to mouse ACE2.

Conclusions:

  • The transition from pre-Omicron to Omicron was not driven by increased ACE2-binding affinity.
  • Enhanced ACE2-binding affinity may have played a role in the evolution and transition of Omicron subvariants.
  • The binding of Alpha and Omicron variants to mouse ACE2 supports a hypothesis of early Omicron evolution originating from the Alpha strain through mutations acquired in mice.
Keywords:
ACE2BindingMouseOmicronSARS-CoV-2Spike protein

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