Potent neutralization of clinical isolates of SARS-CoV-2 D614 and G614 variants by a monomeric, sub-nanomolar affinity nanobody

Nieto, Guillermo Valenzuela; Jara, Ronald; Watterson, Daniel; Modhiran, Naphak; Amarilla, Alberto A.; Himelreichs, Johanna; Khromykh, Alexander A.; Salinas-Rebolledo, Constanza; Pinto, Teresa; Cheuquemilla, Yorka; Margolles, Yago; Rey, Natalia López González del; Miranda-Chacón, Zaray; Cuevas, Alexei; Berking, Anne; Deride, Camila; González-Moraga, Sebastián; Mancilla, Héctor; Maturana, Daniel; Langer, Andreas; Toledo, Juan Pablo; Müller, Ananda; Uberti, Benjamín; Krall, Paola; Ehrenfeld, Pamela; Blesa, Javier; Chaná-Cuevas, Pedro; Rehren, Germán; Schwefel, David; Fernández, Luis A.; Rojas-Fernández, Alejandro

doi:10.1038/s41598-021-82833-w

Cited by 46 publications

(33 citation statements)

References 76 publications

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“…Notwithstanding, the K D remains a key factor to be analyzed. This is the reason why we think our contribution can be helpful to other researchers working in the design and identification of miniproteins and nanobodies against SARS-CoV-2 (52,54,56,57). Having a preliminary screening of the effect of mutations on the binding affinity can help save time and other resources, especially during emergency situations, like the one we are experiencing in the current pandemic.…”

Section: Discussionmentioning

confidence: 91%

Rapid Assessment of Binding Affinity of SARS-COV-2 Spike Protein to the Human Angiotensin-Converting Enzyme 2 Receptor and to Neutralizing Biomolecules Based on Computer Simulations

Buratto

Saxena

et al. 2021

Front. Immunol.

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SARS-CoV-2 infects humans and causes Coronavirus disease 2019 (COVID-19). The S1 domain of the spike glycoprotein of SARS-CoV-2 binds to human angiotensin-converting enzyme 2 (hACE2) via its receptor-binding domain, while the S2 domain facilitates fusion between the virus and the host cell membrane for entry. The spike glycoprotein of circulating SARS-CoV-2 genomes is a mutation hotspot. Some mutations may affect the binding affinity for hACE2, while others may modulate S-glycoprotein expression, or they could result in a virus that can escape from antibodies generated by infection with the original variant or by vaccination. Since a large number of variants are emerging, it is of vital importance to be able to rapidly assess their characteristics: while changes of binding affinity alone do not always cause direct advantages for the virus, they still can provide important insights on where the evolutionary pressure is directed. Here, we propose a simple and cost-effective computational protocol based on Molecular Dynamics simulations to rapidly screen the ability of mutated spike protein to bind to the hACE2 receptor and selected neutralizing biomolecules. Our results show that it is possible to achieve rapid and reliable predictions of binding affinities. A similar approach can be used to perform preliminary screenings of the potential effects of S-RBD mutations, helping to prioritize the more time-consuming and expensive experimental work.

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Section: Discussionmentioning

confidence: 91%

Rapid Assessment of Binding Affinity of SARS-COV-2 Spike Protein to the Human Angiotensin-Converting Enzyme 2 Receptor and to Neutralizing Biomolecules Based on Computer Simulations

Buratto

Saxena

et al. 2021

Front. Immunol.

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“…There are few approved effective treatments for SARS-CoV-2 ( Esparza et al, 2020 ). The treatment of SARS-COV-2 still has many problems to solve ( Valenzuela Nieto et al, 2021 ). Low-cost treatments have important implications for the COVID-19 pandemic ( Ye et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

A SARS-CoV-2 nanobody that can bind to the RBD region may be used for treatment in COVID-19 in animals

Yang

Zhao

et al. 2022

Research in Veterinary Science

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Coronavirus disease 2019 (COVID-19) caused by an infectious virus, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), poses a threat to the world. The suitable treatments must be identified for this disease in animals. Nanobody have therapeutic potential in the COVID-19. In this study, SARS-CoV-2 Spike RBD protein was used to make the nanobody. Nanobodies binding to the SARS-CoV-2 Spike RBD protein was obtained. Interestingly, the nanobody could bind to SARS-CoV-2 Spike S protein and RBD protein at the same time. Nanobodies were validated with a neutralizing antibody detection kit. The use of pseudoviruses confirmed that nanobodies could prevent pseudoviruses from infecting cells. We believe the nanobody are very valuable and could be used in the treatment of COVID-19. SARSCoV-2 nanobodies can be rapidly mass-produced from microorganisms to block SARS-CoV-2 infection in vitro and in vivo with preventive and therapeutic effects.

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“…Secondly, while conventional antibodies that comprise two disulphide-linked polypeptides, heavy and light chain, typically require mammalian cells for production, nanobodies can be manufactured using readily available microbial systems. The potency of nanobodies against SARS-CoV-2 7 infection has been demonstrated in cell-based assays [8][9][10][11][12][13][14][15][16] and most recently in animal studies 17,18 . Several strategies for engineering VHH into a multivalent species are known.…”

mentioning

confidence: 99%

A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

et al. 2021

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SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We report four nanobodies (C5, H3, C1, F2) engineered as homotrimers with pmolar affinity for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Crystal structures show C5 and H3 overlap the ACE2 epitope, whilst C1 and F2 bind to a different epitope. Cryo Electron Microscopy shows C5 binding results in an all down arrangement of the Spike protein. C1, H3 and C5 all neutralize the Victoria strain, and the highly transmissible Alpha (B.1.1.7 first identified in Kent, UK) strain and C1 also neutralizes the Beta (B.1.35, first identified in South Africa). Administration of C5-trimer via the respiratory route showed potent therapeutic efficacy in the Syrian hamster model of COVID-19 and separately, effective prophylaxis. The molecule was similarly potent by intraperitoneal injection.

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Potent neutralization of clinical isolates of SARS-CoV-2 D614 and G614 variants by a monomeric, sub-nanomolar affinity nanobody

Cited by 46 publications

References 76 publications

Rapid Assessment of Binding Affinity of SARS-COV-2 Spike Protein to the Human Angiotensin-Converting Enzyme 2 Receptor and to Neutralizing Biomolecules Based on Computer Simulations

Rapid Assessment of Binding Affinity of SARS-COV-2 Spike Protein to the Human Angiotensin-Converting Enzyme 2 Receptor and to Neutralizing Biomolecules Based on Computer Simulations

A SARS-CoV-2 nanobody that can bind to the RBD region may be used for treatment in COVID-19 in animals

A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

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