scholarly journals In Silico Analyses on the Comparative Potential of Therapeutic Human Monoclonal Antibodies Against Newly Emerged SARS-CoV-2 Variants Bearing Mutant Spike Protein

2022 ◽  
Vol 12 ◽  
Author(s):  
Nabarun Chandra Das ◽  
Pritha Chakraborty ◽  
Jagadeesh Bayry ◽  
Suprabhat Mukherjee
Keyword(s):  
Monoclonal Antibodies ◽  
In Silico ◽  
Spike Protein ◽  
Economic Losses ◽  
Chimeric Antibody ◽  
Stable Complex ◽  
Human Monoclonal Antibodies ◽  
Chimeric Antibodies ◽  
In Silico Analyses ◽  
Potential Use

Since the start of the pandemic, SARS-CoV-2 has already infected more than 250 million people globally, with more than five million fatal cases and huge socio-economic losses. In addition to corticosteroids, and antiviral drugs like remdesivir, various immunotherapies including monoclonal antibodies (mAbs) to S protein of SARS-CoV-2 have been investigated to treat COVID-19 patients. These mAbs were initially developed against the wild-type SARS-CoV-2; however, emergence of variant forms of SARS-CoV-2 having mutations in the spike protein in several countries including India raised serious questions on the potential use of these mAbs against SARS-CoV-2 variants. In this study, using an in silico approach, we have examined the binding abilities of eight mAbs against several SARS-CoV-2 variants of Alpha (B.1.1.7) and Delta (B.1.617.2) lineages. The structure of the Fab region of each mAb was designed in silico and subjected to molecular docking against each mutant protein. mAbs were subjected to two levels of selection based on their binding energy, stability, and conformational flexibility. Our data reveal that tixagevimab, regdanvimab, and cilgavimab can efficiently neutralize most of the SARS-CoV-2 Alpha strains while tixagevimab, bamlanivimab, and sotrovimab can form a stable complex with the Delta variants. Based on these data, we have designed, by in silico, a chimeric antibody by conjugating the CDRH3 of regdanivimab with a sotrovimab framework to combat the variants that could potentially escape from the mAb-mediated neutralization. Our finding suggests that though currently available mAbs could be used to treat COVID-19 caused by the variants of SARS-CoV-2, better results could be expected with the chimeric antibodies.

scholarly journals Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein

2020 ◽  
Vol 26 (9) ◽  
pp. 1422-1427 ◽  
Author(s):  
Seth J. Zost ◽  
Pavlo Gilchuk ◽  
Rita E. Chen ◽  
James Brett Case ◽  
Joseph X. Reidy ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Spike Protein ◽  
Human Monoclonal Antibodies ◽  
Rapid Isolation

scholarly journals Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein

Cell ◽  
2021 ◽  
Author(s):  
Naveenchandra Suryadevara ◽  
Swathi Shrihari ◽  
Pavlo Gilchuk ◽  
Laura A. VanBlargan ◽  
Elad Binshtein ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Spike Protein ◽  
Human Monoclonal Antibodies ◽  
Terminal Domain

scholarly journals Molecular rationale for SARS-CoV-2 spike circulating mutations able to escape bamlanivimab and etesevimab monoclonal antibodies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Erik Laurini ◽  
Domenico Marson ◽  
Suzana Aulic ◽  
Alice Fermeglia ◽  
Sabrina Pricl
Keyword(s):  
Monoclonal Antibodies ◽  
In Silico ◽  
Structural Information ◽  
Viral Evolution ◽  
Protein A ◽  
Immune Surveillance ◽  
Protein S ◽  
Spike Protein ◽  
Wild Type ◽  
Experimental Findings

AbstractThe purpose of this work is to provide an in silico molecular rationale of the role eventually played by currently circulating mutations in the receptor binding domain of the SARS-CoV-2 spike protein (S-RBDCoV‑2) in evading the immune surveillance effects elicited by the two Eli Lilly LY-CoV555/bamlanivimab and LY-CoV016/etesevimab monoclonal antibodies. The main findings from this study show that, compared to the wild-type SARS-CoV-2 spike protein, mutations E484A/G/K/Q/R/V, Q493K/L/R, S494A/P/R, L452R and F490S are predicted to be markedly resistant to neutralization by LY-CoV555, while mutations K417E/N/T, D420A/G/N, N460I/K/S/T, T415P, and Y489C/S are predicted to confer LY-CoV016 escaping advantage to the viral protein. A challenge of our global in silico results against relevant experimental data resulted in an overall 90% agreement. Thus, the results presented provide a molecular-based rationale for all relative experimental findings, constitute a fast and reliable tool for identifying and prioritizing all present and newly reported circulating spike SARS-CoV-2 variants with respect to antibody neutralization, and yield substantial structural information for the development of next-generation vaccines and monoclonal antibodies more resilient to viral evolution.

scholarly journals Human Monoclonal Antibodies against Highly Conserved HR1 and HR2 Domains of the SARS-CoV Spike Protein Are More Broadly Neutralizing

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e50366 ◽  
Author(s):  
Hatem A. Elshabrawy ◽  
Melissa M. Coughlin ◽  
Susan C. Baker ◽  
Bellur S. Prabhakar
Keyword(s):  
Monoclonal Antibodies ◽  
Spike Protein ◽  
Human Monoclonal Antibodies

scholarly journals In silico Antibody Mutagenesis for Optimizing its Binding to the Spike Protein of SARS-CoV-2

2020 ◽  
Author(s):  
Binquan Luan ◽  
Tien Huynh
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Drug Discovery ◽  
In Silico ◽  
Spike Protein ◽  
Computing Power ◽  
Atomic Structures ◽  
Protein Mutagenesis ◽  
Small Molecule Drugs ◽  
Global Pandemic

<p>Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic and there are currently no FDA approved medicines for treatment or prevention. Inspired by promising outcomes for convalescent plasma treatment, developing antibody drugs (biologics) to block SARS-CoV-2 infection has been the focus of drug discovery, along with tremendous efforts in repurposing small-molecule drugs. In the last several months, experimentally, many human neutralizing monoclonal antibodies (mAbs) were successfully extracted from plasma of recovered COVID-19 patients. Currently, several mAbs targeting the SARS-CoV-2's spike protein (Spro) are in clinical trials. With known atomic structures of mAb-Spro complex, it becomes possible to <i>in silico</i> investigate the molecular mechanism of mAb's binding with Spro and design more potent mAbs through protein mutagenesis studies, complementary to existing experimental efforts. Leveraging superb computing power nowadays, we propose a fully automated <i>in silico</i> protocol for quickly identifying possible mutations in a mAb (e.g.~CB6) to enhance its binding affinity with Spro for the design of more efficacious therapeutic mAbs.</p>

scholarly journals Identification of neutralizing human monoclonal antibodies from Italian Covid-19 convalescent patients

2020 ◽  
Author(s):  
Emanuele Andreano ◽  
Emanuele Nicastri ◽  
Ida Paciello ◽  
Piero Pileri ◽  
Noemi Manganaro ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
B Lymphocytes ◽  
Neutralizing Antibodies ◽  
Memory B Cells ◽  
Spike Protein ◽  
Human Monoclonal Antibodies ◽  
Natural Production ◽  
Development Pipeline ◽  
Approved Drugs

ABSTRACTIn the absence of approved drugs or vaccines, there is a pressing need to develop tools for therapy and prevention of Covid-19. Human monoclonal antibodies have very good probability of being safe and effective tools for therapy and prevention of SARS-CoV-2 infection and disease. Here we describe the screening of PBMCs from seven people who survived Covid-19 infection to isolate human monoclonal antibodies against SARS-CoV-2. Over 1,100 memory B cells were single-cell sorted using the stabilized prefusion form of the spike protein and incubated for two weeks to allow natural production of antibodies. Supernatants from each cell were tested by ELISA for spike protein binding, and positive antibodies were further tested for neutralization of spike binding to receptor(s) on Vero E6 cells and for virus neutralization in vitro. From the 1,167 memory B specific for SARS-CoV-2, we recovered 318 B lymphocytes expressing human monoclonals recognizing the spike protein and 74 of these were able to inhibit the binding of the spike protein to the receptor. Finally, 17 mAbs were able to neutralize the virus when assessed for neutralization in vitro. Lead candidates to progress into the drug development pipeline will be selected from the panel of neutralizing antibodies identified with the procedure described in this study.One Sentence SummaryNeutralizing human monoclonal antibodies isolated from Covid-19 convalescent patients for therapeutic and prophylactic interventions.

scholarly journals A conserved immunogenic and vulnerable site on the coronavirus spike protein delineated by cross-reactive monoclonal antibodies

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chunyan Wang ◽  
Rien van Haperen ◽  
Javier Gutiérrez-Álvarez ◽  
Wentao Li ◽  
Nisreen M. A. Okba ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Cross Reactivity ◽  
Cell Entry ◽  
Spike Protein ◽  
Structural Studies ◽  
Human Monoclonal Antibodies ◽  
Human Coronavirus ◽  
Helical Bundle ◽  
Protective Antibodies ◽  
Virion Surface

AbstractThe coronavirus spike glycoprotein, located on the virion surface, is the key mediator of cell entry and the focus for development of protective antibodies and vaccines. Structural studies show exposed sites on the spike trimer that might be targeted by antibodies with cross-species specificity. Here we isolated two human monoclonal antibodies from immunized humanized mice that display a remarkable cross-reactivity against distinct spike proteins of betacoronaviruses including SARS-CoV, SARS-CoV-2, MERS-CoV and the endemic human coronavirus HCoV-OC43. Both cross-reactive antibodies target the stem helix in the spike S2 fusion subunit which, in the prefusion conformation of trimeric spike, forms a surface exposed membrane-proximal helical bundle. Both antibodies block MERS-CoV infection in cells and provide protection to mice from lethal MERS-CoV challenge in prophylactic and/or therapeutic models. Our work highlights an immunogenic and vulnerable site on the betacoronavirus spike protein enabling elicitation of antibodies with unusual binding breadth.

scholarly journals In Silico Molecular-Based Rationale for SARS-CoV-2 Spike Circulating Mutations Able to Escape Bamlanivimab and Etesevimab Monoclonal Antibodies

2021 ◽  
Author(s):  
Erik Laurini ◽  
Domenico Marson ◽  
Suzana Aulic ◽  
Alice Fermeglia ◽  
Sabrina PRICL
Keyword(s):  
Monoclonal Antibodies ◽  
In Silico ◽  
Protective Efficacy ◽  
Protein A ◽  
Immune Surveillance ◽  
Spike Protein ◽  
Wild Type ◽  
Computer Based ◽  
New Challenges ◽  
Experimental Findings

The purpose of this work was to provide an in silico molecular rationale of the role eventually played by currently circulating S-RBDCoV‑2 mutations in evading the immune surveillance effects elicited by the two Eli Lilly LY-CoV555/bamlanivimab and LY-CoV016/etesevimab monoclonal antibodies. The main findings from this study and shows that, compared to the wild-type SARS-CoV-2 spike protein, mutations E484A/G/K/Q/R/V, Q493K/L/R, S494A/P/R, L452R and F490S are predicted to be markedly resistant to neutralization by LY-CoV555, while mutations K417E/N/T, D420A/G/N, N460I/K/S/T, T415P, and Y489C/S are predicted to confer LY-CoV016 escaping advantage to the viral protein. A challenge of our global in silico results against the relevant experimental data resulted in an overall 90% agreement. This achievement not only constitutes a further, robust validation of our computer-based approach but also yields a molecular-based rationale for all relative experimental findings, and leads us to conclude that the current circulating SARS-CoV-2 and all possible emergent variants carrying these mutations in the spike protein can present new challenges for mAb-based therapies and ultimately threaten the fully-protective efficacy of currently available vaccines.

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