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SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor

View ORCID ProfileJiří Zahradník, Shir Marciano, Maya Shemesh, Eyal Zoler, Jeanne Chiaravalli, Björn Meyer, Orly Dym, Nadav Elad, View ORCID ProfileGideon Schreiber
doi: https://doi.org/10.1101/2021.01.06.425392
Jiří Zahradník
1Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
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  • ORCID record for Jiří Zahradník
Shir Marciano
1Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
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Maya Shemesh
1Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
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Eyal Zoler
1Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
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Jeanne Chiaravalli
2Chemogenomic and Biological Screening Core Facility Institut Pasteur, 75724 Paris, France
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Björn Meyer
3Viral Populations and Pathogenesis Unit CNRS UMR 3569 Institut Pasteur, 75724 Paris, France
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Orly Dym
4Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel
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Nadav Elad
5Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 7610001, Israel
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Gideon Schreiber
1Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
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  • ORCID record for Gideon Schreiber
  • For correspondence: gideon.schreiber@weizmann.ac.il
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Abstract

SARS-CoV-2 is constantly evolving, with more contagious mutations spreading rapidly. Using in vitro evolution to affinity maturate the receptor-binding domain (RBD) of the spike protein towards ACE2, resulted in the more contagious mutations, S477N, E484K, and N501Y to be among the first selected. This includes the British and South-African variants. Plotting the binding affinity to ACE2 of all RBD mutations against their incidence in the population shows a strong correlation between the two. Further in vitro evolution enhancing binding by 600-fold provides guidelines towards potentially new evolving mutations with even higher infectivity. For example, Q498R in combination with N501Y. This said, the high-affinity RBD is also an efficient drug, inhibiting SARS-CoV-2 infection. The 2.9Å Cryo-EM structure of the high-affinity complex, including all rapidly spreading mutations provides structural basis for future drug and vaccine development and for in silico evaluation of known antibodies.

Competing Interest Statement

The authors J.Z. and G.S. declare the US Provisional Patent Application No. 63/125,984 (Yeda Ref.: 2020-091).

Footnotes

  • This version of the manuscript has been revised to update the Abstract.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 08, 2021.
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SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor
Jiří Zahradník, Shir Marciano, Maya Shemesh, Eyal Zoler, Jeanne Chiaravalli, Björn Meyer, Orly Dym, Nadav Elad, Gideon Schreiber
bioRxiv 2021.01.06.425392; doi: https://doi.org/10.1101/2021.01.06.425392
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SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor
Jiří Zahradník, Shir Marciano, Maya Shemesh, Eyal Zoler, Jeanne Chiaravalli, Björn Meyer, Orly Dym, Nadav Elad, Gideon Schreiber
bioRxiv 2021.01.06.425392; doi: https://doi.org/10.1101/2021.01.06.425392

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