scholarly journals Molecular insights into receptor binding of recent emerging SARS-CoV-2 variants

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pengcheng Han ◽  
Chao Su ◽  
Yanfang Zhang ◽  
Chongzhi Bai ◽  
Anqi Zheng ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Binding Affinity ◽  
Receptor Binding ◽  
Molecular Basis ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Molecular Information ◽  
Alpha Beta ◽  
Key Residues ◽  
Novel Therapeutic

AbstractMultiple SARS-CoV-2 variants of concern (VOCs) have been emerging and some have been linked to an increase in case numbers globally. However, there is yet a lack of understanding of the molecular basis for the interactions between the human ACE2 (hACE2) receptor and these VOCs. Here we examined several VOCs including Alpha, Beta, and Gamma, and demonstrate that five variants receptor-binding domain (RBD) increased binding affinity for hACE2, and four variants pseudoviruses increased entry into susceptible cells. Crystal structures of hACE2-RBD complexes help identify the key residues facilitating changes in hACE2 binding affinity. Additionally, soluble hACE2 protein efficiently prevent most of the variants pseudoviruses. Our findings provide important molecular information and may help the development of novel therapeutic and prophylactic agents targeting these emerging mutants.

scholarly journals Computational Prediction of the Epitopes of HA1 Protein of Influenza Viruses to its Neutralizing Antibodies

Antibodies ◽  
2018 ◽  
Vol 8 (1) ◽  
pp. 2
Author(s):  
Xiaoyan Zeng ◽  
Fiona Legge ◽  
Chao Huang ◽  
Xiao Zhang ◽  
Yongjun Jiao ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Crystal Structures ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Computational Prediction ◽  
Binding Domain ◽  
Influenza Viruses ◽  
New Method ◽  
Receptor Binding Domain ◽  
Antibody Recognition

In this work, we have used a new method to predict the epitopes of HA1 protein of influenza virus to several antibodies HC19, CR9114, BH151 and 4F5. While our results reproduced the binding epitopes of H3N2 or H5N1 for the neutralizing antibodies HC19, CR9114, and BH151 as revealed from the available crystal structures, additional epitopes for these antibodies were also suggested. Moreover, the predicted epitopes of H5N1 HA1 for the newly developed antibody 4F5 are located at the receptor binding domain, while previous study identified a region 76-WLLGNP-81 as the epitope. The possibility of antibody recognition of influenza virus via different mechanism by binding to different epitopes of an antigen is also discussed.

scholarly journals Characterization of Phytochemicals in Ulva intestinalis L. and Their Action Against SARS-CoV-2 Spike Glycoprotein Receptor-Binding Domain

2021 ◽  
Vol 9 ◽  
Author(s):  
Seema A. Kulkarni ◽  
Sabari B.B. Krishnan ◽  
Bavya Chandrasekhar ◽  
Kaushani Banerjee ◽  
Honglae Sohn ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Density Functional ◽  
Human Life ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Conceptual Density Functional Theory ◽  
Marine Microalga ◽  
Ulva Intestinalis ◽  
Novel Therapeutic Strategies

Coronavirus disease-2019 (COVID-19) has caused a severe impact on almost all aspects of human life and economic development. Numerous studies are being conducted to find novel therapeutic strategies to overcome COVID-19 pandemic in a much effective way. Ulva intestinalis L. (Ui), a marine microalga, known for its antiviral property, was considered for this study to determine the antiviral efficacy against severe acute respiratory syndrome-associated Coronavirus-2 (SARS-CoV-2). The algal sample was dried and subjected to ethanolic extraction, followed by purification and analysis using gas chromatography-coupled mass spectrometry (GC-MS). Forty-three known compounds were identified and docked against the S1 receptor binding domain (RBD) of the spike (S) glycoprotein. The compounds that exhibited high binding affinity to the RBD of S1 protein were further analyzed for their chemical behaviour using conceptual density-functional theory (C-DFT). Finally, pharmacokinetic properties and drug-likeliness studies were carried out to test if the compounds qualified as potential leads. The results indicated that mainly phenols, polyenes, phytosteroids, and aliphatic compounds from the extract, such as 2,4-di-tert-butylphenol (2,4-DtBP), doconexent, 4,8,13-duvatriene-1,3-diol (DTD), retinoyl-β-glucuronide 6′,3′-lactone (RBGUL), and retinal, showed better binding affinity to the target. Pharmacokinetic validation narrowed the list to 2,4-DtBP, retinal and RBGUL as the possible antiviral candidates that could inhibit the viral spike protein effectively.

scholarly journals Enhancement of SARS-CoV-2 Receptor Binding Domain -CR3022 Human Antibody Binding Affinity via in Silico Engineering Approach

2020 ◽  
Author(s):  
Fateme Sefid ◽  
Zahra Payandeh ◽  
Ghasem Azamirad ◽  
Behzad Mansoori ◽  
Behzad Baradaran ◽  
...  
Keyword(s):  
Amino Acids ◽  
Binding Affinity ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Affinity Maturation ◽  
Binding Domain ◽  
Human Antibody ◽  
Receptor Binding Domain ◽  
Receptor Binding Site ◽  
Specificity And Sensitivity

Abstract Background: The nCoV-2019 is a cause of COVID-19 disease. The surface spike glycoprotein (S), which is necessary for virus entry through the intervention of the host receptor and it mediates virus-host membrane fusion, is the primary coronavirus antigen (Ag). The angiotensin-converting enzyme 2 (ACE2) is reported to be the effective human receptor for SARS-CoVs 2. ACE2 receptor can be prevented by neutralizing antibodies (nAbs) such as CR3022 targeting the virus receptor-binding site. Considering the importance of computational docking, and affinity maturation we aimed to find the important amino acids of the CR3022 antibody (Ab). These amino acids were then replaced by other amino acids to improve Ab-binding affinity to a receptor-binding domain (RBD) of the 2019-nCoV spike protein. Finally, we measured the binding affinity of Ab variants to the Ag. Result: Our findings disclosed that several variant mutations could successfully improve the characteristics of the Ab binding compared to the normal antibodies. Conclusion: The modified antibodies may be possible candidates for stronger affinity binding to Ags which in turn can affect the specificity and sensitivity of antibodies.

scholarly journals Application of an integrated computational antibody engineering platform to design SARS-CoV-2 neutralizers

2021 ◽  
Author(s):  
Saleh Riahi ◽  
Jae Hyeon Lee ◽  
Shuai Wei ◽  
Robert Cost ◽  
Alessandro Masiero ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
In Silico ◽  
Half Life ◽  
Neutralizing Antibodies ◽  
Binding Domain ◽  
Antibody Engineering ◽  
Receptor Binding Domain ◽  
Effector Functions

Abstract As the COVID-19 pandemic continues to spread, hundreds of new initiatives including studies on existing medicines are running to fight the disease. To deliver a potentially immediate and lasting treatment to current and emerging SARS-CoV-2 variants, new collaborations and ways of sharing are required to create as many paths forward as possible. Here we leverage our expertise in computational antibody engineering to rationally design/engineer three previously reported SARS-CoV neutralizing antibodies and share our proposal towards anti-SARS-CoV-2 biologics therapeutics. SARS-CoV neutralizing antibodies, m396, 80R, and CR-3022 were chosen as templates due to their diversified epitopes and confirmed neutralization potency against SARS-CoV (but not SARS-CoV-2 except for CR3022). Structures of variable fragment (Fv) in complex with receptor binding domain (RBD) from SARS-CoV or SARS-CoV-2 were subjected to our established in silico antibody engineering platform to improve their binding affinity to SARS-CoV-2 and developability profiles. The selected top mutations were ensembled into a focused library for each antibody for further screening. In addition, we convert the selected binders with different epitopes into the trispecific format, aiming to increase potency and to prevent mutational escape. Lastly, to avoid antibody induced virus activation or enhancement, we suggest application of NNAS and DQ mutations to the Fc region to eliminate effector functions and extend half-life.

scholarly journals Potent SARS-CoV-2 Neutralizing Antibodies Directed Against Spike N-Terminal Domain Target a Single Supersite

2021 ◽  
Author(s):  
Gabriele Cerutti ◽  
Yicheng Guo ◽  
Tongqing Zhou ◽  
Jason Gorman ◽  
Myungjin Lee ◽  
...  
Keyword(s):  
Free Surface ◽  
Crystal Structures ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Viral Membrane ◽  
Terminal Domain ◽  
Flexible Loops

SummaryNumerous antibodies that neutralize SARS-CoV-2 have been identified, and these generally target either the receptor-binding domain (RBD) or the N-terminal domain (NTD) of the viral spike. While RBD-directed antibodies have been extensively studied, far less is known about NTD-directed antibodies. Here we report cryo-EM and crystal structures for seven potent NTD-directed neutralizing antibodies in complex with spike or isolated NTD. These structures defined several antibody classes, with at least one observed in multiple convalescent donors. The structures revealed all seven antibodies to target a common surface, bordered by glycans N17, N74, N122, and N149. This site – formed primarily by a mobile β-hairpin and several flexible loops – was highly electropositive, located at the periphery of the spike, and the largest glycan-free surface of NTD facing away from the viral membrane. Thus, in contrast to neutralizing RBD-directed antibodies that recognize multiple non-overlapping epitopes, potent NTD-directed neutralizing antibodies target a single supersite.

scholarly journals Identifying the Zoonotic Origin of SARS-CoV-2 by Modeling the Binding Affinity between the Spike Receptor-Binding Domain and Host ACE2

2020 ◽  
Vol 19 (12) ◽  
pp. 4844-4856
Author(s):  
Xiaoqiang Huang ◽  
Chengxin Zhang ◽  
Robin Pearce ◽  
Gilbert S. Omenn ◽  
Yang Zhang
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Binding Domain ◽  
Receptor Binding Domain

scholarly journals Key Residues of the Receptor Binding Domain in the Spike Protein of SARS-CoV-2 Mediating the Interactions with ACE2: A Molecular Dynamics Study

Nanoscale ◽  
2021 ◽  
Author(s):  
Yanmei Yang ◽  
Yunju Zhang ◽  
Yuanyuan Qu ◽  
Chao Zhang ◽  
Xuewei Liu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Global Health ◽  
Receptor Binding ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Wide Spread ◽  
Key Residues

The wide spread of coronavirus disease 2019 (COVID-19) has declared a global health emergency. As one of the most important targets for antibody and drug developments, Spike RBD-ACE2 interface has...

scholarly journals Application of an integrated computational antibody engineering platform to design SARS-CoV-2 neutralizers

2021 ◽  
Author(s):  
Saleh Riahi ◽  
Jae Hyeon Lee ◽  
Shuai Wei ◽  
Robert Cost ◽  
Alessandro Masiero ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
In Silico ◽  
Half Life ◽  
Neutralizing Antibodies ◽  
Binding Domain ◽  
Antibody Engineering ◽  
Receptor Binding Domain ◽  
Effector Functions

As the COVID-19 pandemic continues to spread, hundreds of new initiatives including studies on existing medicines are running to fight the disease. To deliver a potentially immediate and lasting treatment to current and emerging SARS-CoV-2 variants, new collaborations and ways of sharing are required to create as many paths forward as possible. Here we leverage our expertise in computational antibody engineering to rationally design/optimize three previously reported SARS-CoV neutralizing antibodies and share our proposal towards anti-SARS-CoV-2 biologics therapeutics. SARS-CoV neutralizing antibodies, m396, 80R, and CR-3022 were chosen as templates due to their diversified epitopes and confirmed neutralization potency against SARS. Structures of variable fragment (Fv) in complex with receptor binding domain (RBD) from SARS-CoV or SARS-CoV2 were subjected to our established in silico antibody engineering platform to improve their binding affinity to SARS-CoV2 and developability profiles. The selected top mutations were ensembled into a focused library for each antibody for further screening. In addition, we convert the selected binders with different epitopes into the trispecific format, aiming to increase potency and to prevent mutational escape. Lastly, to avoid antibody induced virus activation or enhancement, we applied NNAS and DQ mutations to the Fc region to eliminate effector functions and extend half-life.

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