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Designing peptides predicted to bind to the omicron variant better than ACE2 via computational protein design and

Thassanai Sitthiyotha1, Wantanee Treewattanawong1, Surasak Chunsrivirot1

  • 1Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok, Thailand.

Plos One
|October 10, 2023
PubMed

Insights

Novel peptides were designed to inhibit the Omicron variant of SARS-CoV-2 by blocking its binding to human cells. These designed peptides show promising therapeutic potential against COVID-19, outperforming existing inhibitors.

Area of Science:

  • Biochemistry
  • Computational Biology
  • Drug Discovery

Background:

  • The COVID-19 pandemic, caused by SARS-CoV-2, has led to significant global mortality.
  • The emergence of SARS-CoV-2 variants, such as Omicron, poses ongoing public health challenges.
  • Inhibition of the interaction between the SARS-CoV-2 receptor-binding domain (RBD) and ACE2 receptor is a key therapeutic strategy.

Purpose of the Study:

  • To design novel peptide inhibitors targeting the Omicron variant's RBD using computational protein design.
  • To enhance the binding affinity and stability of designed peptides compared to natural ACE2 and existing inhibitors.
  • To identify promising peptide candidates for developing new COVID-19 therapies.

Main Methods:

  • Computational protein design (CPD) was employed to generate 25-mer peptide binders (SPB25) based on the ACE2 receptor's α1 helix.
  • Molecular dynamics (MD) simulations and MM-GBSA calculations were used to predict binding affinities (ΔGbind) and assess peptide stability.
  • The binding interactions between designed peptides and Omicron RBD were analyzed to optimize favorable interactions with conserved residues.

Main Results:

  • Two novel peptides, SPB25T7L/K11A and SPB25T7L/K11L, demonstrated superior binding affinities to Omicron RBD compared to native ACE2 and a previously studied peptide (SPB25).
  • Predicted binding affinities (ΔGbind (MM‑GBSA)) for the top peptides were -92.4 ± 0.4 and -95.7 ± 0.5 kcal/mol, respectively.
  • The designed peptides exhibited enhanced predicted stability and favorable binding interactions with conserved Omicron RBD residues.

Conclusions:

  • The designed SPB25 peptides are effective inhibitors of Omicron RBD binding to ACE2.
  • These peptides represent promising therapeutic candidates for combating Omicron variant infections.
  • The study highlights the potential of CPD in developing novel antiviral agents against emerging SARS-CoV-2 variants.

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