Covalently Engineered Protein Minibinders with Enhanced Neutralization Efficacy against Escaping SARS-CoV-2 Variants

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

The rapid emergence and spread of escaping mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly challenged our efforts in fighting against the COVID-19 pandemic. A broadly neutralizing reagent against these concerning variants is thus highly desirable for the prophylactic and therapeutic treatments of SARS-CoV-2 infection. We herein report a covalent engineering strategy on protein minibinders for potent neutralization of the escaping variants such as B.1.617.2 (Delta), B.1.617.1 (Kappa), and B.1.1.529 (Omicron) through in situ cross-linking with the spike receptor binding domain (RBD). The resulting covalent minibinder (GlueBinder) exhibited enhanced blockage of RBD-human angiotensin-converting enzyme 2 (huACE2) interaction and more potent neutralization effect against the Delta variant than its noncovalent counterpart as demonstrated on authentic virus. By leveraging the covalent chemistry against escaping mutations, our strategy may be generally applicable for restoring and enhancing the potency of neutralizing antibodies to SARS-CoV-2 and other rapidly evolving viral targets.

Related collections

Most cited references 30

Record: found
Abstract: found
Article: not found

Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization

Delphine Planas, David Veyer, Artem Baidaliuk … (2021)

The SARS-CoV-2 B.1.617 lineage was identified in October 2020 in India1-5. Since then, it has become dominant in some regions of India and in the UK, and has spread to many other countries6. The lineage includes three main subtypes (B1.617.1, B.1.617.2 and B.1.617.3), which contain diverse mutations in the N-terminal domain (NTD) and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein that may increase the immune evasion potential of these variants. B.1.617.2-also termed the Delta variant-is believed to spread faster than other variants. Here we isolated an infectious strain of the Delta variant from an individual with COVID-19 who had returned to France from India. We examined the sensitivity of this strain to monoclonal antibodies and to antibodies present in sera from individuals who had recovered from COVID-19 (hereafter referred to as convalescent individuals) or who had received a COVID-19 vaccine, and then compared this strain with other strains of SARS-CoV-2. The Delta variant was resistant to neutralization by some anti-NTD and anti-RBD monoclonal antibodies, including bamlanivimab, and these antibodies showed impaired binding to the spike protein. Sera collected from convalescent individuals up to 12 months after the onset of symptoms were fourfold less potent against the Delta variant relative to the Alpha variant (B.1.1.7). Sera from individuals who had received one dose of the Pfizer or the AstraZeneca vaccine had a barely discernible inhibitory effect on the Delta variant. Administration of two doses of the vaccine generated a neutralizing response in 95% of individuals, with titres three- to fivefold lower against the Delta variant than against the Alpha variant. Thus, the spread of the Delta variant is associated with an escape from antibodies that target non-RBD and RBD epitopes of the spike protein.

0 comments Cited 1147 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Adaptive immunity to SARS-CoV-2 and COVID-19

Alessandro Sette, Shane Crotty (2021)

The adaptive immune system is important for control of most viral infections. The three fundamental components of the adaptive immune system are B cells (the source of antibodies), CD4+ T cells, and CD8+ T cells. The armamentarium of B cells, CD4+ T cells, and CD8+ T cells has differing roles in different viral infections, and in vaccines, and thus it is critical to directly study adaptive immunity to SARS-CoV-2 to understand COVID-19. Knowledge is now available on relationships between antigen-specific immune responses and SARS-CoV-2 infection. While more studies are needed, a picture has begun to emerge that reveals that CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to control of SARS-CoV-2, in both non-hospitalized and hospitalized cases of COVID-19. The specific functions and kinetics of these adaptive immune responses are discussed, as well as their interplay with innate immunity and implications for COVID-19 vaccines and immune memory against re-infection.

0 comments Cited 858 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies

Yunlong Cao, Jing WANG, Fanchong Jian … (2021)

The SARS-CoV-2 B.1.1.529 (Omicron) variant contains 15 mutations of the receptor-binding domain (RBD). How Omicron evades RBD-targeted neutralizing antibodies requires immediate investigation. Here we use high-throughput yeast display screening 1,2 to determine the profiles of RBD escaping mutations for 247 human anti-RBD neutralizing antibodies and show that the neutralizing antibodies can be classified by unsupervised clustering into six epitope groups (A–F)—a grouping that is highly concordant with knowledge-based structural classifications 3–5 . Various single mutations of Omicron can impair neutralizing antibodies of different epitope groups. Specifically, neutralizing antibodies in groups A–D, the epitopes of which overlap with the ACE2-binding motif, are largely escaped by K417N, G446S, E484A and Q493R. Antibodies in group E (for example, S309) 6 and group F (for example, CR3022) 7 , which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but a subset of neutralizing antibodies are still escaped by G339D, N440K and S371L. Furthermore, Omicron pseudovirus neutralization showed that neutralizing antibodies that sustained single mutations could also be escaped, owing to multiple synergetic mutations on their epitopes. In total, over 85% of the tested neutralizing antibodies were escaped by Omicron. With regard to neutralizing-antibody-based drugs, the neutralization potency of LY-CoV016, LY-CoV555, REGN10933, REGN10987, AZD1061, AZD8895 and BRII-196 was greatly undermined by Omicron, whereas VIR-7831 and DXP-604 still functioned at a reduced efficacy. Together, our data suggest that infection with Omicron would result in considerable humoral immune evasion, and that neutralizing antibodies targeting the sarbecovirus conserved region will remain most effective. Our results inform the development of antibody-based drugs and vaccines against Omicron and future variants.

0 comments Cited 858 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): J Am Chem Soc

Journal ID (iso-abbrev): J Am Chem Soc

Journal ID (publisher-id): ja

Journal ID (coden): jacsat

Title: Journal of the American Chemical Society

Publisher: American Chemical Society

ISSN (Print): 0002-7863

ISSN (Electronic): 1520-5126

Publication date (Electronic): 25 February 2022

Electronic Location Identifier: jacs.1c11554

Affiliations

[† ]Synthetic and Functional Biomolecules Center, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University , Beijing 100871, China

[‡ ]Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University , Beijing 100871, China

[§ ]Shenzhen Bay Laboratory , Shenzhen 518055, China

[∥ ]State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences , Wuhan, Hubei 430071, China

[⊥ ]Department of Microorganism Engineering, Beijing Institute of Biotechnology , Beijing 100071, China

[¶ ]Department of Pharmacy, Peking University Third Hospital , Beijing 100191, China

Author notes

[* ] wangml@ 123456wh.iov.cn

[* ] linjian@ 123456pku.edu.cn

[* ] pengchen@ 123456pku.edu.cn

Author information

Yu Han https://orcid.org/0000-0002-0553-5413

Long Chen https://orcid.org/0000-0002-7802-5094

Jian Lin https://orcid.org/0000-0002-1519-9679

Peng R. Chen https://orcid.org/0000-0002-0402-7417

Article

DOI: 10.1021/jacs.1c11554

PMC ID: 8905923

PubMed ID: 35212528

SO-VID: 805596be-cd16-4a92-b455-cfec693e51d5

License:

This article is made available via the PMC Open Access Subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

History

Date received : 01 November 2021

Funding

Funded by: Tencent, doi 10.13039/100015803;

Award ID: NA

Funded by: Natural Science Foundation of Beijing Municipality, doi 10.13039/501100004826;

Award ID: Z200010

Funded by: Ministry of Science and Technology of the People''s Republic of China, doi 10.13039/501100002855;

Award ID: 2021YFC0863300

Funded by: Ministry of Science and Technology of the People''s Republic of China, doi 10.13039/501100002855;

Award ID: 2018ZX09711003

Funded by: Ministry of Science and Technology of the People''s Republic of China, doi 10.13039/501100002855;

Award ID: 2016YFA0501500

Funded by: National Natural Science Foundation of China, doi 10.13039/501100001809;

Award ID: 21937001

Funded by: National Natural Science Foundation of China, doi 10.13039/501100001809;

Award ID: 21740001

Custom metadata

document-id-old-9 ja1c11554

document-id-new-14 ja1c11554

ccc-price

ScienceOpen disciplines: Chemistry

Data availability:

ScienceOpen disciplines: Chemistry

Comments

Comment on this article

scite_

Cited by 11

See all cited by

Most referenced authors 510

See all reference authors

Covalently Engineered Protein Minibinders with Enhanced Neutralization Efficacy against Escaping SARS-CoV-2 Variants

Read this article at

Abstract

Related collections

Novel Coronavirus Disease COVID-19

Most cited references 30

Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization

Adaptive immunity to SARS-CoV-2 and COVID-19

Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 304

Cited by 11

Most referenced authors 510