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SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor
Open accessPreprint — published as 10.1038/s41564-021-00954-4
Abstract
SARS-CoV-2 is continually 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, explaining the convergent evolution of the “European” (20E-EU1), “British” (501.V1),”South African” (501.V2), and ‘‘Brazilian” variants (501.V3). 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 epistatic to N501Y. Nevertheless, 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 a structural basis for future drug and vaccine development and for in silico evaluation of known antibodies.
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“The RBD mutation N501Y, which increases affinity to ACE2 and is present in B.1.1.7 and B.1.351(ref.20 ), does not impair on its own post-vaccine serum neutralization 21 .”
From Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies (2021) · cites this paper as [20]
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“To assess the potential to resist future mutations, highly neutralizing Nbs were also evaluated for their binding to a potential future RBD variant (RBD62 with 9 point mutations), which was identified by in vitro evolution for ultrahigh-affinity ACE2 binding 27 .”
Science's Response to CoVID‐19
Long, M. J. C., & Aye, Y. (2021) · ChemMedChem · doi:10.1002/cmdc.202100079 · Cited by 22
Jiang, Y., Quan, L., Li, K., Li, Y., Zhou, Y., Wu, T., & Lyu, Q. (2023) · IEEE Transactions on Computational Biology and Bioinformatics · doi:10.1109/tcbb.2022.3233627 · Cited by 21
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Chen, Y., Yang, W., Chen, H., Huang, L., Gao, J.-Y., Lin, C., Wang, Y.-C., Yang, C., Liu, Y., Hou, M., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101658 · Cited by 30
“Vero E6 cells, a common cell line for the SARS-CoV-2 study, have high ACE2 expression levels but with low TMPRSS2 expression.”
InfluentialGenomic reconstruction of the SARS-CoV-2 epidemic in EnglandPreprint
Vöhringer, H. S., Sanderson, T., Sinnott, M., et al. (2021) · medRxiv · doi:10.1101/2021.05.22.21257633 · Cited by 29
Abbas, Q., Викторович, К. А., Sharrouf, K. A., Jyakhwo, S., & Komissarov, A. S. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.02.25.481941 · Cited by 19
“3] In combination with N501Y increases affinity to ACE2 [43].”
BackgroundBerus, S., Nowicka, A., Wieruszewska, J., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119706 · Cited by 14
Immunogenic amino acid motifs and linear epitopes of COVID-19 mRNA vaccines
Wisnewski, A. V., Redlich, C. A., Kamath, K., Abad, Q.-A., Smith, R., Fazen, L. E., Santiago, R., Liu, J., Luna, J. C., Martinez, B., et al. (2021) · PLoS ONE · doi:10.1371/journal.pone.0252849 · Cited by 16
“Nonetheless, the RBD is an important target of neutralizing antibodies that develop in vivo during natural infection [33], and possibly a driver for the evolution of mutations given its critical role in the virus life cycle [34, 35].”
BackgroundWidera, M., Mühlemann, B., Corman, V. M., Toptan, T., Beheim-Schwarzbach, J., Kohmer, N., Schneider, J. A., Berger, A., Veith, T., Pallas, C., et al. (2021) · Microorganisms · doi:10.3390/microorganisms9040748 · Cited by 13
“7 was predicted to be more transmissible [4].”
BackgroundXiao, C., Mao, L., Wang, Z., Gao, L., Zhu, G., Su, J., Chen, X., Yuan, J., Hu, Y., Yin, Z., et al. (2022) · iScience · doi:10.1016/j.isci.2022.103934 · Cited by 21
B-Cell Memory Responses to Variant Viral Antigens
White, H. N. (2021) · Viruses · doi:10.3390/v13040565 · Cited by 18
The limits of SARS-CoV-2 predictability
Baker, R. E., Park, S. W., Wagner, C. E., & Metcalf, C. J. E. (2021) · Nature Ecology & Evolution · doi:10.1038/s41559-021-01514-z · Cited by 12
On the Evolutionary Trajectory of SARS-CoV-2: Host Immunity as a Driver of Adaptation in RNA Viruses
Warger, J., & Gaudieri, S. (2022) · Viruses · doi:10.3390/v15010070 · Cited by 11
Nikitin, P. A., DiMuzio, J. M., Dowling, J. P., Patel, N. B., Bingaman, J. L., Heimbach, B. C., Henriquez, N., Nicolescu, C., Polley, A. M., Sikorski, E. L., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abl9943 · Cited by 13
“K356 participates in the formation of a hydrophobic pocket in the RBD (38) that may explain its functional importance and evolutionary conservation.”
BackgroundImmune response variables and viral mutations impact on COVID-19 reinfection and relapse
Sanaie, S., Golipour, E., Shamekh, A., Sadaie, M. R., Mahmoodpoor, A., & Yousefi, M. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.108108 · Cited by 12
Umair, M., Ikram, A., Salman, M., Badar, N., Haider, S. A., Rehman, Z., Ammar, M., Rana, M. S., & Ali, Q. (2021) · medRxiv · doi:10.1101/2021.07.14.21259909 · Cited by 9
“The RBD mutations enhance infectivity due to presence of L452R and T478K by increasing the spike protein's affinity for the human ACE2 receptor [11, 12].”
BackgroundPokhrel, S., Kraemer, B. R., Lee, L., Samardzic, K., & Mochly‐Rosen, D. (2021) · PLoS ONE · doi:10.1371/journal.pone.0251426 · Cited by 12
“7 variant was shown to have higher affinity for hACE2 along with a lower dissociation rate constant [30].”
BackgroundLemmermann, N. A. W., Lieb, B., Laufs, T., Renzaho, A., Runkel, S., Kohnen, W., Linke, M., Gerber, S., Schweiger, S., Michel, A., et al. (2021) · medRxiv · doi:10.1101/2021.02.11.21251324 · Cited by 9
“K417 is a unique ACE2-interacting residue outside of the RBM. Amino acid changes N501Y and E484K enhance the binding affinity of the S protein to ACE2 which might be correlated to the epidemiologically observed higher infectivity and transmission (Zahradnik et al. 2021).”
BackgroundFive Challenges in the Field of Viral Diversity and Evolution
Sanjuán, R., Illingworth, C. J. R., Geoghegan, J. L., Iranzo, J., Zwart, M. P., Ciota, A. T., Moratorio, G., Gago‐Zachert, S., Duffy, S., & Vijaykrishna, D. (2021) · Frontiers in Virology · doi:10.3389/fviro.2021.684949 · Cited by 24
“For instance, the recurrent emergence of certain variants both in laboratory evolution experiments and in nature can help us predict the evolution of some viral features (8, 9).”
BackgroundReplicative fitness SARS-CoV-2 20I/501Y.V1 variant in a human reconstituted bronchial epithelium
Touret, F., Luciani, L., Baronti, C., et al. (2021) · bioRxiv · doi:10.1101/2021.03.22.436427 · Cited by 9
“This may be explained by the presence of the 85 N501Y mutation in the receptor binding domain (RBD) of the spike protein which enhances 86 viral particle binding to the ACE2 receptor (9).”
BackgroundShrivastava, S., Mhaske, S. T., Modak, M. S., Virkar, R., Pisal, S. S., Mishra, A. C., & Arankalle, V. A. (2022) · Archives of Virology · doi:10.1007/s00705-021-05320-7 · Cited by 7
“In in-vitro experiments, an increased binding affinity of the T478K mutant for the ACE2 receptor has been shown [27].”
BackgroundSARS-CoV-2 convergent evolution as a guide to explore adaptive advantagePreprint
Zahradník, J., Nunvář, J., & Schreiber, G. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.05.24.445534 · Cited by 6
Self-citationBarton, M. I., MacGowan, S., Kutuzov, M. A., Dushek, O., Barton, G., & van der Merwe, P. A. (2021) · bioRxiv · doi:10.1101/2021.05.18.444646 · Cited by 9
“…Rambaut et al., 2020), suggesting that they confer a selective advantage, rather than emerged by chance, such as through a founder effect. were the main mutations that appeared following random RBD mutagenesis and in vitro selection of mutants with enhanced ACE2 binding (Zahradník et al., 2021).”
BackgroundInfluential2020 Hindsight: Should evolutionary virologists have expected the unexpected during a pandemic?
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A Closed-Form, Analytical Approximation for Apparent Surface Charge and Electric Field of Molecules
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Schepens, B., van Schie, L., Nerinckx, W., Roose, K., Breedam, W. V., Fijałkowska, D., Devos, S., Weyts, W., Cae, S. D., Vanmarcke, S., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.08.433449 · Cited by 7
Zahradník, J., & Schreiber, G. (2021) · Biochemistry · doi:10.1021/acs.biochem.1c00356 · Cited by 4
Self-citationUltrafast topological data analysis reveals pandemic-scale dynamics of convergent evolutionPreprint
Bleher, M., Hahn, L., Neumann, M., Ardern, Z., Patiño-Galindo, J. Á., Carrière, M., Bauer, U., Rabadán, R., & Ott, A. (2021) · medRxiv · doi:10.1101/2021.06.10.21258550 · Cited by 3
“One approach to identify potential adaptive mutations is by experimentally mutating many positions and testing the effect of these mutations in certain phenotypes, like binding to the human receptor or immune escape [9, 35, 45].”
BackgroundEnsovibep, a novel trispecific DARPin candidate that protects against SARS-CoV-2 variantsPreprint
Rothenberger, S., Hurdiss, D. L., Walser, M., Malvezzi, F., Mayor, J., Ryter, S., Moreno, H., Liechti, N., Bosshart, A., Iss, C., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.03.429164 · Cited by 17
May Vaccines Select SARS-Cov-2 Variants More Readily Escaping Immunity - An Analysis of Public Data
Tan, M., Lounnas, V., Azalbert, X., et al. (2021) · doi:10.26502/ami.93650065 · Cited by 4
Potential differentiation of successive SARS-CoV-2 mutations by RNA: DNA hybrid analyses
He, L., Xie, Z., Long, X., Zhang, C., Ma, K., & She, L. (2023) · Biophysical Chemistry · doi:10.1016/j.bpc.2023.107013 · Cited by 3
Worldwide SARS-CoV-2 haplotype distribution in early pandemic
Cairo, A., Iorio, M. V., Spena, S., Tagliabue, E., & Peyvandi, F. (2022) · PLoS ONE · doi:10.1371/journal.pone.0263705 · Cited by 5
IPD 2.0: To derive insights from an evolving SARS-CoV-2 genome
Desai, S., Rane, A., Joshi, A., & Dutt, A. (2021) · BMC Bioinformatics · doi:10.1186/s12859-021-04172-x · Cited by 6
“V1) emerging in the UK [15], B.1.351 (clade 20H/501Y.V2) in South Africa [16], and P.1 (clade 20J/501Y.V3) in Brazil [17] that were found to harbour a total of 32, 25 and 25 median mutations across 13, 82 and 13 samples, respectively, for each lineage (Additional file 1: Tables S3 and S4).”
BackgroundInfluentialThe Development of Epitope-Based Recombinant Protein Vaccines against SARS-CoV-2
Khalid, K., Lim, H. X., Hwang, J. S., & Poh, C. L. (2024) · The AAPS Journal · doi:10.1208/s12248-024-00963-1 · Cited by 3
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CovRadar: Continuously tracking and filtering SARS-CoV-2 mutations for molecular surveillancePreprint
Wittig, A., Miranda, F. M., Hölzer, M., Altenburg, T., Bartoszewicz, J. M., Beyvers, S., Dieckmann, M. A., Genske, U., Giese, S. H., Nowicka, M., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.03.429146 · Cited by 2
The basis of a more contagious 501Y.V1 variant of SARS-COV-2
Liu, H.-L., Zhang, Q.-Q., Wei, P., et al. (2021) · bioRxiv · doi:10.1101/2021.02.02.428884 · Cited by 2
Immunoediting in SARS-CoV-2: Mutual relationship between the virus and the host
Kheshtchin, N., Bakhshi, P., Arab, S., & Nourizadeh, M. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.108531 · Cited by 2
Zainulabid, U. A., Yassim, A. S. M., Soffian, S. N., et al. (2021) · medRxiv · doi:10.1101/2021.08.11.21261902 · Cited by 1
Nikitin, P. A., DiMuzio, J. M., Dowling, J. P., Patel, N. B., Bingaman, J. L., Heimbach, B. C., Henriquez, N., Nicolescu, C., Polley, A. M., Sikorski, E. L., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.10.18.464900 · Cited by 1
Metadata
- Authors
- Zahradník, J., Marciano, S., Shemesh, M., Zoler, E., Chiaravalli, J., Meyer, B., Rudich, Y., Dym, O., Elad, N., & Schreiber, G.
- Affiliations
- Weizmann Institute of Science (IL)
- Institut Pasteur (FR)
- Corresponding author
- Schreiber, Gideon
- ORCID
- Venue
- Nature Microbiology
- Publisher
- openRxiv
- Published
- 2021-01-06
- Volume
- 6
- Issue
- 9
- Pages
- 1188-1198
- ISSN
- 2058-5276 (ISSN-L)
- OpenAlex
- W3193682077
- Cited by
- 458
- References
- 0
- Citations by year
- 2026: 14 · 2025: 27 · 2024: 42 · 2023: 82 · 2022: 177 · 2021: 103
- FWCI
- 32.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Microbiology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (acceptedVersion, cc-by)
- HAL (submittedVersion)
- Funders
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Weizmann Institute of Science
- Israel Science Foundation (3814/19)
- Nature
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 detection and testing
- Keywords
- SARS-CoV-2, spike protein receptor-binding domain, ACE2 binding affinity, in vitro evolution, affinity maturation, SARS-CoV-2 variants, E484K, N501Y, antiviral drug design, hamster challenge model, COVID-19 pandemic, vaccine development
- MeSH terms
- Protein Domains, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Animals, Antiviral Agents, Female, Cricetinae, Humans, Male, Mesocricetus, Mutation, Protein Binding, Receptors, Virus, Drug Design, Evolution, Molecular, Virus Internalization, Molecular Dynamics Simulation, Spike Glycoprotein, Coronavirus
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