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Engineered ACE2 receptor traps potently neutralize SARS-CoV-2.

Anum Glasgow1, Jeff Glasgow2, Daniel Limonta3,4

  • 1Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158.

Proceedings of the National Academy of Sciences of the United States of America
|October 23, 2020
PubMed
Summary

Researchers engineered a soluble angiotensin-converting enzyme II (ACE2) decoy receptor that potently neutralizes SARS-CoV-2 by blocking viral spike protein binding. This engineered ACE2 variant offers a promising therapeutic strategy against SARS-CoV-2 and other ACE2-using coronaviruses.

Keywords:
SARS-CoV-2antiviral therapeuticscomputational designreceptor trapyeast display

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Area of Science:

  • Biochemistry
  • Virology
  • Protein Engineering

Background:

  • Severe acute respiratory syndrome coronavirus (SARS-CoV) entry into host cells relies on the interaction between the viral spike protein and the human angiotensin-converting enzyme II (ACE2) receptor.
  • Developing effective countermeasures against SARS-CoV-2 is crucial for global health.

Purpose of the Study:

  • To engineer optimized, enzymatically inactivated ACE2 variants that act as potent inhibitors of SARS-CoV-2 infection.
  • To create high-affinity receptor traps that bind the SARS-CoV-2 spike protein's receptor binding domain (RBD).

Main Methods:

  • Computational design of the ACE2-RBD interface using a two-stage flexible protein backbone approach.
  • Affinity maturation through random mutagenesis and yeast surface display selection.
  • Fusion of engineered ACE2 variants with collectrin and Fc domains to enhance stability and avidity.

Main Results:

  • Computational design improved ACE2-RBD binding affinity by up to 12-fold.
  • Further affinity maturation yielded a variant with 170-fold higher binding affinity to the RBD compared to wild-type ACE2.
  • Engineered ACE2 receptor traps demonstrated potent neutralization of SARS-CoV-2 with IC50s in the 10-100 ng/mL range.

Conclusions:

  • Engineered ACE2 receptor traps are a promising therapeutic strategy against SARS-CoV-2 and other ACE2-utilizing coronaviruses.
  • This approach offers a rapid response capability for future viral threats by predesigning receptor traps.
  • Viral resistance to these traps would likely also impede viral entry, enhancing their therapeutic potential.