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TitleSARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution.
Journal, issue, pagesNat Microbiol, Vol. 6, Issue 9, Page 1188-1198, Year 2021
Publish dateAug 16, 2021
AuthorsJiří Zahradník / Shir Marciano / Maya Shemesh / Eyal Zoler / Daniel Harari / Jeanne Chiaravalli / Björn Meyer / Yinon Rudich / Chunlin Li / Ira Marton / Orly Dym / Nadav Elad / Mark G Lewis / Hanne Andersen / Matthew Gagne / Robert A Seder / Daniel C Douek / Gideon Schreiber /
PubMed AbstractSARS-CoV-2 variants of interest and concern will continue to emerge for the duration of the COVID-19 pandemic. To map mutations in the receptor-binding domain (RBD) of the spike protein that affect ...SARS-CoV-2 variants of interest and concern will continue to emerge for the duration of the COVID-19 pandemic. To map mutations in the receptor-binding domain (RBD) of the spike protein that affect binding to angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, we applied in vitro evolution to affinity-mature the RBD. Multiple rounds of random mutagenic libraries of the RBD were sorted against decreasing concentrations of ACE2, resulting in the selection of higher affinity RBD binders. We found that mutations present in more transmissible viruses (S477N, E484K and N501Y) were preferentially selected in our high-throughput screen. Evolved RBD mutants include prominently the amino acid substitutions found in the RBDs of B.1.620, B.1.1.7 (Alpha), B1.351 (Beta) and P.1 (Gamma) variants. Moreover, the incidence of RBD mutations in the population as presented in the GISAID database (April 2021) is positively correlated with increased binding affinity to ACE2. Further in vitro evolution increased binding by 1,000-fold and identified mutations that may be more infectious if they evolve in the circulating viral population, for example, Q498R is epistatic to N501Y. We show that our high-affinity variant RBD-62 can be used as a drug to inhibit infection with SARS-CoV-2 and variants Alpha, Beta and Gamma in vitro. In a model of SARS-CoV-2 challenge in hamster, RBD-62 significantly reduced clinical disease when administered before or after infection. A 2.9 Å cryo-electron microscopy structure of the high-affinity complex of RBD-62 and ACE2, including all rapidly spreading mutations, provides a structural basis for future drug and vaccine development and for in silico evaluation of known antibodies.
External linksNat Microbiol / PubMed:34400835
MethodsEM (single particle)
Resolution2.9 Å
Structure data

12187

7bh9

EMDB-12187, PDB-7bh9:
SARS-CoV-2 RBD-62 in complex with ACE2 peptidase domain
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • severe acute respiratory syndrome coronavirus 2
KeywordsVIRUS / In vitro evolution / Complex / receptor binding domain

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