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Engineered ACE2 receptor traps potently neutralize SARS-CoV-2
Anum Glasgow; Jeff Edward Glasgow; Daniel Limonta; Paige Solomon; Irene Lui; Yang Zhang; Matthew A Nix; Nicholas J Rettko; Shion A Lim; Shoshana Zha; Rachel Yamin; Kevin Kao; Oren S Rosenberg; Jeffrey V Ravetch; Arun P Wiita; Kevin K Leung; Xin X Zhou; Tom C Hobman; Tanja K Kortemme; James A. Wells.
Afiliación
  • Anum Glasgow; University of California, San Francisco
  • Jeff Edward Glasgow; University of California, San Francisco
  • Daniel Limonta; University of Alberta
  • Paige Solomon; University of California, San Francisco
  • Irene Lui; University of California, San Francisco
  • Yang Zhang; University of California, San Francisco
  • Matthew A Nix; University of California, San Francisco
  • Nicholas J Rettko; University of California, San Francisco
  • Shion A Lim; University of California, San Francisco
  • Shoshana Zha; University of California, San Francisco
  • Rachel Yamin; Rockefeller University
  • Kevin Kao; Rockefeller University
  • Oren S Rosenberg; University of California, San Francisco
  • Jeffrey V Ravetch; Rockefeller University
  • Arun P Wiita; University of California, San Francisco
  • Kevin K Leung; UCSF
  • Xin X Zhou; University of California, San Francisco
  • Tom C Hobman; University of Alberta
  • Tanja K Kortemme; University of California, San Francisco
  • James A. Wells; University of California, San Francisco
Preprint en En | PREPRINT-BIORXIV | ID: ppbiorxiv-231746
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ABSTRACT
An essential mechanism for SARS-CoV-1 and -2 infection begins with the viral spike protein binding to the human receptor protein angiotensin-converting enzyme II (ACE2). Here we describe a stepwise engineering approach to generate a set of affinity optimized, enzymatically inactivated ACE2 variants that potently block SARS-CoV-2 infection of cells. These optimized receptor traps tightly bind the receptor binding domain (RBD) of the viral spike protein and prevent entry into host cells. We first computationally designed the ACE2-RBD interface using a two-stage flexible protein backbone design process that improved affinity for the RBD by up to 12-fold. These designed receptor variants were affinity matured an additional 14-fold by random mutagenesis and selection using yeast surface display. The highest affinity variant contained seven amino acid changes and bound to the RBD 170-fold more tightly than wild-type ACE2. With the addition of the natural ACE2 collectrin domain and fusion to a human Fc domain for increased stabilization and avidity, the most optimal ACE2 receptor traps neutralized SARS-CoV-2 pseudotyped lentivirus and authentic SARS-CoV-2 virus with half-maximal inhibitory concentrations (IC50) in the 10-100 ng/ml range. Engineered ACE2 receptor traps offer a promising route to fighting infections by SARS-CoV-2 and other ACE2-utilizing coronaviruses, with the key advantage that viral resistance would also likely impair viral entry. Moreover, such traps can be pre-designed for viruses with known entry receptors for faster therapeutic response without the need for neutralizing antibodies isolated or generated from convalescent patients.
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Texto completo: 1 Colección: 09-preprints Base de datos: PREPRINT-BIORXIV Tipo de estudio: Rct Idioma: En Año: 2020 Tipo del documento: Preprint
Texto completo
Añadir a Mi BVS
Imprimir
XML
Buscar en Google
Texto completo: 1 Colección: 09-preprints Base de datos: PREPRINT-BIORXIV Tipo de estudio: Rct Idioma: En Año: 2020 Tipo del documento: Preprint