Development of a Series of Neutralizing Nanobodies against SARS-CoV-2 Spike Protein

V. A. Zhuchkov; Жучков В. А.; S. V. Ivanov; Иванов С. В.; J. E. Kravchenko; Кравченко Ю. Е.; S. P. Chumakov; Чумаков С. П.

doi:10.31857/S0026898423030230

Development of a Series of Neutralizing Nanobodies against SARS-CoV-2 Spike Protein

Authors: Zhuchkov V.A.¹, Ivanov S.V.¹, Kravchenko J.E.¹, Chumakov S.P.¹
Affiliations:
1. Shemyakin‒Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
Issue: Vol 57, No 3 (2023)
Pages: 505-516
Section: МОЛЕКУЛЯРНАЯ БИОЛОГИЯ КЛЕТКИ
URL: https://journals.rcsi.science/0026-8984/article/view/138635
DOI: https://doi.org/10.31857/S0026898423030230
EDN: https://elibrary.ru/CIBRDB
ID: 138635

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Abstract
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Abstract

Countering the spread of new respiratory infections and reducing the damage they cause to society requires efficient strategies for rapid development of targeted therapeutics, such as monoclonal antibodies. Nanobodies, defined as variable fragments of heavy-chain camelid antibodies, have a set of characteristics that make them particularly convenient for this purpose. The speed at which the SARS-CoV-2 pandemic had spread has confirmed that a key factor in the development of therapeutics is obtaining highly effective blocking agents as soon as possible, as well as the diversity of epitopes to which these agents bind. We have optimized the process of selection of blocking nanobodies from the genetic material of camelids and obtained a panel of nanobody structures with affinity to spike protein in the lower nanomolar and picomolar ranges and high binding specificity. The subset of nanobodies that demonstrate the ability to block the interaction between the spike protein and the cellular ACE2 receptor was selected in experiments in vitro and in vivo. It has been established that the epitopes bound by the nanobodies are located in the RBD domain of the spike protein and have little overlap. The diversity of binding regions may allow the mixture of nanobodies to retain potential therapeutic efficacy towards new variants of the spike protein, and the structural features of nanobodies, in particular, their compact size and high stability, indicate the possibility of their utilization in the form of aerosols.

Keywords

nanobodies, SARS-CoV-2, spike protein, RBD, ACE2, neutralizing antibodies, monoclonal antibody, immunotherapy

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