scholarly journals Computational Design of Stapled Peptide Inhibitor against SARS-CoV-2 Receptor Binding Domain

2021 ◽  
Author(s):  
Asha Rani Choudhury ◽  
Atanu Maity ◽  
Sayantani Chakraborty ◽  
Rajarshi Chakrabarti
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Computational Design ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Conformational Restriction ◽  
Stapled Peptides ◽  
Stapled Peptide ◽  
Free Peptide ◽  
The One

Since its first detection in 2019, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been the cause of millions of deaths worldwide. Despite the development and administration of different vaccines, the situation is still worrisome as the virus is constantly mutating to produce newer variants some of which are highly infectious. This raises an urgent requirement to understand the infection mechanism and thereby design therapeutic-based treatment for COVID-19. The gateway of the virus to the host cell is mediated by the binding of the Receptor Binding Domain (RBD) of the virus spike protein to the Angiotensin-Converting Enzyme 2 (ACE2) of the human cell. Therefore, the RBD of SARS-CoV-2 can be used as a target to design therapeutics. The α1 helix of ACE2 which forms direct contact with the RBD surface has been used as a template in the current study to design stapled peptide therapeutics. Using computer simulation, the mechanism and thermodynamics of the binding of six stapled peptides with RBD have been estimated. Among these, the one with two lactam stapling agents has shown binding affinity, sufficient to overcome RBD-ACE2 binding. Analyses of the mechanistic detail reveal that a reorganization of amino acids at the RBD-ACE2 interface produces favorable enthalpy of binding whereas conformational restriction of the free peptide reduces the loss in entropy to result in higher binding affinity. The understanding of the relation of the nature of the stapling agent with their binding affinity opens up the avenue to explore stapled peptides as therapeutic against SARS-CoV-2.

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 Molecular Dynamics of SARS-CoV-2 Delta Variant Receptor Binding Domain in Complex with ACE2 Receptor

2021 ◽  
Author(s):  
Victor Padilla-Sanchez
Keyword(s):  
Molecular Dynamics ◽  
At Risk ◽  
Receptor Binding ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Virus Variant ◽  
Structural Interactions ◽  
The One ◽  
Shed Light ◽  
Human Receptor

COVID19 pandemic has disrupted our lives since December 2019 causing millions of infections and deaths worldwide. After more than a year we have vaccines that are effective in preventing the disease even though we are far from finished to vaccinate most of the population. Certain countries are doing better vaccinating people while others are far behind and if that is not enough new variants have appeared that put at risk our progress on defeating COVID19. The virus SARS-CoV-2 is mutating and many mutations change the spike glycoprotein which binds to the human receptor ACE2 sometimes making the virus more infectious and able to evade immunity. One virus variant of concern (VoC) is the one called delta which is becoming prevalent very quickly among new infections. The delta variant is a real threat for many people that are not vaccinated. Here I present molecular dynamics of the receptor binding domain in complex with its receptor ACE2 to shed light on the structural interactions that make this variant more dangerous.

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 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 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.

scholarly journals Identifying zoonotic origin of SARS-CoV-2 by modeling the binding affinity between Spike receptor-binding domain and host ACE2

2020 ◽  
Author(s):  
Xiaoqiang Huang ◽  
Chengxin Zhang ◽  
Robin Pearce ◽  
Gilbert S. Omenn ◽  
Yang Zhang
Keyword(s):  
Intermediate Host ◽  
Binding Affinity ◽  
Receptor Binding ◽  
Limited Range ◽  
Binding Domain ◽  
Binding Energies ◽  
Host Cells ◽  
Research Progress ◽  
Receptor Binding Domain ◽  
Intermediate Hosts

ABSTRACTDespite considerable research progress on SARS-CoV-2, the direct zoonotic origin (intermediate host) of the virus remains ambiguous. The most definitive approach to identify the intermediate host would be the detection of SARS-CoV-2-like coronaviruses in wild animals. However, due to the high number of animal species, it is not feasible to screen all the species in the laboratory. Given that the recognition of the binding ACE2 proteins is the first step for the coronaviruses to invade host cells, we proposed a computational pipeline to identify potential intermediate hosts of SARS-CoV-2 by modeling the binding affinity between the Spike receptor-binding domain (RBD) and host ACE2. Using this pipeline, we systematically examined 285 ACE2 variants from mammals, birds, fish, reptiles, and amphibians, and found that the binding energies calculated on the modeled Spike-RBD/ACE2 complex structures correlate closely with the effectiveness of animal infections as determined by multiple experimental datasets. Built on the optimized binding affinity cutoff, we suggested a set of 96 mammals, including 48 experimentally investigated ones, which are permissive to SARS-CoV-2, with candidates from primates, rodents, and carnivores at the highest risk of infection. Overall, this work not only suggested a limited range of potential intermediate SARS-CoV-2 hosts for further experimental investigation; but more importantly, it proposed a new structure-based approach to general zoonotic origin and susceptibility analyses that are critical for human infectious disease control and wildlife protection.

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