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Protein Scaffold-Based Multimerization of Soluble ACE2 Efficiently Blocks SARS-CoV-2 Infection In Vitro and In Vivo.

Alisan Kayabolen1, Ugur Akcan1, Doğancan Özturan1

  • 1Koç University Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, 34450, Turkey.

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Summary
This summary is machine-generated.

Multimeric soluble ACE2 (sACE2) decoys show over 100-fold improved SARS-CoV-2 neutralization compared to monomeric versions. These potent decoys effectively neutralize variants and protect mice, offering a promising therapeutic strategy.

Keywords:
MoonTagSARS-CoV-2SunTagdecoy receptorsescape mutationsmultimerizationneutralizationsACE2

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Area of Science:

  • Virology
  • Biochemistry
  • Immunology

Background:

  • Soluble ACE2 (sACE2) decoys are explored for SARS-CoV-2 inhibition, but their potency is limited.
  • Escape mutations pose a challenge to the efficacy of current antiviral strategies.

Purpose of the Study:

  • To develop highly potent multimeric sACE2 decoys using SunTag or MoonTag systems.
  • To evaluate the neutralization efficiency of multimeric sACE2 against SARS-CoV-2, including variants of concern.
  • To assess the therapeutic efficacy of multimeric sACE2 in a preclinical model.

Main Methods:

  • Construction of multimeric sACE2 using SunTag and MoonTag protein scaffolds.
  • Assessment of neutralization activity in pseudoviral systems and against clinical SARS-CoV-2 isolates.
  • Evaluation of efficacy against SARS-CoV-2 variants (Delta, Omicron).
  • In vivo therapeutic treatment in a mouse model of SARS-CoV-2 infection.

Main Results:

  • Multimeric sACE2 demonstrated over 100-fold greater neutralization efficiency than monomeric sACE2.
  • SunTag/MoonTag-fused sACE2 achieved sub-nanomolar IC50 values, comparable to monoclonal antibodies.
  • Efficient neutralization of pseudoviruses with mutations from Delta and Omicron variants.
  • Therapeutic administration of sACE2(v1)-MoonTag provided protection in a mouse model.

Conclusions:

  • Highly potent multimeric sACE2 decoys effectively neutralize SARS-CoV-2, including variants.
  • These multimeric decoys exhibit significantly enhanced potency compared to monomeric forms.
  • Multimeric sACE2 represents a promising therapeutic candidate for treating SARS-CoV-2 infections.