scholarly journals in silico Assessment of Antibody Drug Resistance to Bamlanivimab of SARS-CoV-2 Variant B.1.617

2021 ◽  
Author(s):  
Leili Zhang ◽  
Tien Huynh ◽  
Binquan Luan
Keyword(s):  
Molecular Mechanism ◽  
Viral Entry ◽  
In Silico ◽  
Md Simulation ◽  
Point Of View ◽  
Host Cells ◽  
Receptor Binding Domain ◽  
Nonlocal Effects ◽  
Angiotensin Converting Enzyme 2 ◽  
Human Antibodies

The highly infectious SARS-CoV-2 variant B.1.617 with double mutations E484Q and L452R in the receptor binding domain (RBD) of SARS-CoV-2's spike protein is worrisome. Demonstrated in crystal structures, the residues 452 and 484 in RBD are not in direct contact with interfacial residues in the angiotensin converting enzyme 2 (ACE2). This suggests that albeit there are some possibly nonlocal effects, the E484Q and L452R mutations might not significantly affect RBD's binding with ACE2, which is an important step for viral entry into host cells. Thus, without the known molecular mechanism, these two successful mutations (from the point of view of SARS-CoV-2) can be hypothesized to evade human antibodies. Using in silico all-atom molecular dynamics (MD) simulation as well as deep learning (DL) approaches, here we show that these two mutations significantly reduce the binding affinity between RBD and the antibody LY-CoV555 (also named as Bamlanivimab) that was proven to be efficacious for neutralizing the wide-type SARS-CoV-2. With the revealed molecular mechanism on how L452R and E484K evade LY-CoV555, we expect that more specific therapeutic antibodies can be accordingly designed and/or a precision mixing of antibodies can be achieved in a cocktail treatment for patients infected with the variant B.1.617.

scholarly journals A Potential Peptide Inhibitor of SARS-CoV‑2 S and human ACE2 Complex.

2020 ◽  
Author(s):  
Grijesh Jaiswal ◽  
Veerendra Kumar
Keyword(s):  
Human Cell ◽  
Viral Entry ◽  
Md Simulation ◽  
Cell Receptor ◽  
Docking Studies ◽  
Peptide Inhibitor ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Potential Therapeutics

Abstract The disease COVID-19 has caused heavy socio-economic burden and there is urgent need to control the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic. The viral entry into human cell depends on the attachment of spike (S) protein to human cell receptor angiotensin-converting enzyme 2 (ACE2). We have designed a peptide inhibitor (ΔABP- α2) targeting the receptor binding domain (RBD) of S protein using in silico approach. Docking studies and computed affinities suggest peptide inhibitor binds at the RBD with 10-fold higher affinity than hACE2. MD simulation confirm the stable binding of inhibitor to hACE2. Immunoinformatic studies non-immunogenic nature of peptide. Thus, the proposed peptide could serve potential therapeutics for viral infection.

scholarly journals Allosteric Cross-Talk Among SARS-CoV-2 Spike’s Receptor-Binding Domain Mutations Triggers an Effective Hijacking of Human Cell Receptor

2021 ◽  
Author(s):  
Angelo Spinello ◽  
Andrea Saltalamacchia ◽  
Jure Borišek ◽  
Alessandra Magistrato
Keyword(s):  
Receptor Binding ◽  
Viral Entry ◽  
Cell Receptor ◽  
Binding Domain ◽  
Host Cells ◽  
Evolutionary Strategies ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Societal Challenge ◽  
Dynamics Simulations

ABSTRACTThe rapid and relentless emergence of novel highly transmissible SARS-CoV-2 variants, possibly decreasing vaccine efficacy, currently represents a formidable medical and societal challenge. These variants frequently hold mutations on the Spike protein’s Receptor-Binding Domain (RBD), which, binding to the Angiotensin-Converting Enzyme 2 (ACE2) receptor, mediates viral entry into the host cells.Here, all-atom Molecular Dynamics simulations and Dynamical Network Theory of the wild-type and mutant RBD/ACE2 adducts disclose that while the N501Y mutation (UK variant) enhances the Spike’s binding affinity towards ACE2, the N501Y, E484K and K417N mutations (South African variant) aptly adapt to increase SARS-CoV-2 propagation via a two-pronged strategy: (i) effectively grasping ACE2 through an allosteric signaling between pivotal RBD structural elements; and (ii) impairing the binding of antibodies elicited by infected/vaccinated patients. This information, unlocking the molecular terms and evolutionary strategies underlying the increased virulence of emerging SARS-CoV-2 variants, set the basis for developing the next-generation anti-COVID-19 therapeutics.TOC GRAPHICS

scholarly journals Molecular Mechanism of the N501Y Mutation for Enhanced Binding between SARS-CoV-2’s Spike Protein and Human ACE2 Receptor

2021 ◽  
Author(s):  
Binquan Luan ◽  
Haoran Wang ◽  
Tien Huynh
Keyword(s):  
Molecular Mechanism ◽  
Hydrophobic Interactions ◽  
Neutralizing Antibody ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Global Pandemic ◽  
Dynamics Simulations ◽  
Antibody Cocktail

AbstractCoronavirus disease 2019 (COVID-19) has been an ongoing global pandemic for over a year. Recently, an emergent SARS-CoV-2 variant (B.1.1.7) with an unusually large number of mutations had become highly contagious and wide-spreading in United Kingdom. From genome analysis, the N501Y mutation within the receptor binding domain (RBD) of the SARS-CoV-2’s spike protein might have enhanced the viral protein’s binding with the human angiotensin converting enzyme 2 (hACE2). The latter is the prelude for the virus’ entry into host cells. So far, the molecular mechanism of this enhanced binding is still elusive, which prevents us from assessing its effects on existing therapeutic antibodies. Using all atom molecular dynamics simulations, we demonstrated that Y501 in mutated RBD can be well coordinated by Y41 and K353 in hACE2 through hydrophobic interactions, increasing the overall binding affinity between RBD and hACE2 by about 0.81 kcal/mol. We further explored how the N501Y mutation might affect the binding between a neutralizing antibody (CB6) and RBD. We expect that our work can help researchers design proper measures responding to this urgent virus mutation, such as adding a modified/new neutralizing antibody specifically targeting at this variant in the therapeutic antibody cocktail.Abstract Figure

scholarly journals Investigation of Interaction Between the Spike Protein of SARS-CoV-2 and ACE2-Expressing Cells Using an In Vitro Cell Capturing System

2021 ◽  
Author(s):  
Yuning Shang ◽  
Feixiang Chen ◽  
Shasha Li ◽  
Lijuan Song ◽  
Yunzhen Gao ◽  
...  
Keyword(s):  
Viral Entry ◽  
Living Cells ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Protein Variant ◽  
In Vitro System ◽  
Angiotensin Converting Enzyme 2

Abstract Background: The Interaction between severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ) spike protein with Angiotensin converting enzyme 2 (ACE2) on the host cells is a crucial step for the viral entry and infection. Therefore, investigating the molecular mechanism underlying the interaction is of great importance for the prevention of the infection of SARS-CoV-2. In this study, we aimed to establish a virus-free in vitro system to study the interaction between the spike protein and host cells of SARS-CoV-2.Results: Our results show that ACE2-overexpressing HEK293T cells are captured by immobilized spike protein, and the cell capturing process can be inhibited by the receptor binding domain of the spike protein or antibodies against S protein. Furthermore, spike protein variant with D614G mutant show a higher cell capturing ability than wild type spike protein. In addition, the captured cells can be eluted as living cells for further investigation.Conclusions: This study provides a new in vitro system for investigating the interaction between SARS-CoV-2 and host cells and purifying ACE2-expressing cells.

scholarly journals A Fungal Defensin Targets the SARS−CoV−2 Spike Receptor−Binding Domain

2021 ◽  
Vol 7 (7) ◽  
pp. 553
Author(s):  
Bin Gao ◽  
Shunyi Zhu
Keyword(s):  
Receptor Binding ◽  
Viral Entry ◽  
Single Point ◽  
Binding Domain ◽  
Host Cells ◽  
Single Point Mutation ◽  
Binding Motif ◽  
Microsporum Canis ◽  
Receptor Binding Domain ◽  
Fungal Defensin

Coronavirus Disease 2019 (COVID−19) elicited by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS−CoV−2) is calling for novel targeted drugs. Since the viral entry into host cells depends on specific interactions between the receptor−binding domain (RBD) of the viral Spike protein and the membrane−bound monocarboxypeptidase angiotensin converting enzyme 2 (ACE2), the development of high affinity RBD binders to compete with human ACE2 represents a promising strategy for the design of therapeutics to prevent viral entry. Here, we report the discovery of such a binder and its improvement via a combination of computational and experimental approaches. The binder micasin, a known fungal defensin from the dermatophytic fungus Microsporum canis with antibacterial activity, can dock to the crevice formed by the receptor−binding motif (RBM) of RBD via an extensive shape complementarity interface (855.9 Å2 in area) with numerous hydrophobic and hydrogen−bonding interactions. Using microscale thermophoresis (MST) technique, we confirmed that micasin and its C−terminal γ−core derivative with multiple predicted interacting residues exhibited a low micromolar affinity to RBD. Expanding the interface area of micasin through a single point mutation to 970.5 Å2 accompanying an enhanced hydrogen bond network significantly improved its binding affinity by six−fold. Our work highlights the naturally occurring fungal defensins as an emerging resource that may be suitable for the development into antiviral agents for COVID−19.

Metainflammation in COVID-19

2022 ◽  
Vol 22 ◽  
Author(s):  
Mojtaba Bakhtiari ◽  
Kamyar Asadipooya
Keyword(s):  
Cell Membrane ◽  
Viral Entry ◽  
Virus Entry ◽  
Host Cells ◽  
Elderly Men ◽  
Virus Binding ◽  
Angiotensin Converting Enzyme 2 ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Binding Capability

Abstract: A new coronavirus pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2], has been on the rise. This virus is fatal for broad groups of populations, including elderly, men, and patients with comorbidities among which obesity is a possible risk factor. The pathophysiologic connections between obesity/metainflammation and COVID-19 may be directly related to increasing soluble ACE2 (angiotensin-converting enzyme 2] levels which potentiates the viral entrance into the host cells, or indirectly related to dysregulation of immune system, microvascular injury and hypercoagulability. The SARS-CoV-2 S-glycoprotein interacts mainly with ACE2 or possibly DDP4 receptors to enter into the host cells. The host proteases, especially TMPRSS2 (transmembrane protease serine 2], support the fusion process and virus entry. While membranous ACE2 is considered a port of entry to the cell for SARS-CoV-2, it seems that soluble ACE2 retains its virus binding capability and enhances its entry into the cells. Interestingly, ACE2 on cell membrane may have protective roles by diminishing cytokine storm-related injuries to the organs. Applying medications that can reduce soluble ACE2 levels, antagonizing TMPRSS2 or blocking DDP4 can improve the outcomes of COVID-19. Metformin and statins through immunomodulatory activities, Orlistat by reducing viral replication, and thiazolidinediones by upregulating ACE2 expression have potential beneficial effects against COVID-19. However, the combination of dipeptidyl peptidase-4 (DDP4] inhibitors and spironolactone/eplerenone seems to be more effective by reducing soluble ACE2 level, antagonizing TMPRSS2, maintaining ACE2 on cell membrane and reducing risk of viral entry into the cells.

Impact of the B.1.1.7 variant on neutralizing monoclonal antibodies recognizing diverse epitopes on SARS–CoV–2 Spike

2021 ◽  
Author(s):  
Carl Graham ◽  
Jeffrey Seow ◽  
Isabella Huettner ◽  
Hataf Khan ◽  
Neophytos Kouphou ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Infectious Virus ◽  
Antigenic Drift ◽  
Host Cells ◽  
Receptor Binding Domain ◽  
Neutralization Activity ◽  
Neutralizing Activity ◽  
Neutralizing Epitopes

The interaction of the SARS–CoV–2 Spike receptor binding domain (RBD) with the ACE2 receptor on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS–CoV–2 variants has revealed mutations arising in the RBD, the N–terminal domain (NTD) and S2 subunits of Spike. To fully understand how these mutations affect the antigenicity of Spike, we have isolated and characterized neutralizing antibodies targeting epitopes beyond the already identified RBD epitopes. Using recombinant Spike as a sorting bait, we isolated >100 Spike–reactive monoclonal antibodies from SARS–CoV–2 infected individuals. ≈45% showed neutralizing activity of which ≈20% were NTD–specific. None of the S2–specific antibodies showed neutralizing activity. Competition ELISA revealed that NTD–specific mAbs formed two distinct groups: the first group was highly potent against infectious virus, whereas the second was less potent and displayed glycan–dependant neutralization activity. Importantly, mutations present in B.1.1.7 Spike frequently conferred resistance to neutralization by the NTD–specific neutralizing antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes need to be considered when investigating antigenic drift in emerging variants.

Cross-neutralization antibodies against SARS-CoV-2 and RBD mutations from convalescent patient antibody libraries

2020 ◽  
Author(s):  
Yan Lou ◽  
Wenxiang Zhao ◽  
Haitao Wei ◽  
Min Chu ◽  
Ruihua Chao ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Therapeutic Agents ◽  
Therapeutic Interventions ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Human Antibodies ◽  
Global Pandemic ◽  
Antibody Libraries ◽  
Cross Neutralization

AbstractThe emergence of coronavirus disease 2019 (COVID-19) pandemic led to an urgent need to develop therapeutic interventions. Among them, neutralizing antibodies play crucial roles for preventing viral infections and contribute to resolution of infection. Here, we describe the generation of antibody libraries from 17 different COVID-19 recovered patients and screening of neutralizing antibodies to SARS-CoV-2. After 3 rounds of panning, 456 positive phage clones were obtained with high affinity to RBD (receptor binding domain). Then the positive clones were sequenced and reconstituted into whole human IgG for epitope binning assays. After that, all 19 IgG were classified into 6 different epitope groups or Bins. Although all these antibodies were shown to have ability to bind RBD, the antibodies in Bin2 have more superiority to inhibit the interaction between spike protein and angiotensin converting enzyme 2 receptor (ACE2). Most importantly, the antibodies from Bin2 can also strongly bind with mutant RBDs (W463R, R408I, N354D, V367F and N354D/D364Y) derived from SARS-CoV-2 strain with increased infectivity, suggesting the great potential of these antibodies in preventing infection of SARS-CoV-2 and its mutations. Furthermore, these neutralizing antibodies strongly restrict the binding of RBD to hACE2 overexpressed 293T cells. Consistently, these antibodies effectively neutralized pseudovirus entry into hACE2 overexpressed 293T cells. In Vero-E6 cells, these antibodies can even block the entry of live SARS-CoV-2 into cells at only 12.5 nM. These results suggest that these neutralizing human antibodies from the patient-derived antibody libraries have the potential to become therapeutic agents against SARS-CoV-2 and its mutants in this global pandemic.

scholarly journals Covalent Bonding Aptamer with Enhanced SARS-CoV-2 RBD-ACE2 Blocking and Pseudovirus Neutralization Activities

2021 ◽  
Author(s):  
Zichen Qin ◽  
Yiying Zhu ◽  
Yu Xiang
Keyword(s):  
Covalent Bonding ◽  
Host Cells ◽  
Receptor Binding Domain ◽  
Covalent Bonds ◽  
Angiotensin Converting Enzyme 2 ◽  
Drug Candidates ◽  
Chemically Modified ◽  
Binding Interface ◽  
Covalent Inhibition ◽  
Protein Receptor

SARS-CoV-2 uses its spike protein receptor-binding domain (RBD) to interact with the angiotensin-converting enzyme 2 (ACE2) receptor on host cells. Inhibitors of the RBD-ACE2 interaction are therefore promising drug candidates in treating COVID-19. Here, we report a covalent bonding aptamer that can block the RBD-ACE2 interaction and neutralize SARS-CoV-2 pseudovirus infection by forming covalent bonds on RBD, resulting in more than 25-fold enhancement of pseudovirus neutralization efficacy over the original binding aptamer. The chemically modified aptamer is equipped with sulfur(VI) fluoride exchange (SuFEx) modifications and covalently targets important RBD residues within the RBD-ACE2 binding interface, including Y453 and R408. The covalent bonding is highly specific to RBD over other proteins such as human serum albumin (HSA), ACE2 and immunoglobulin G1 (IgG1) Fc. Our study demonstrates the promise of introducing covalent inhibition mechanisms for developing robust RBD-ACE2 inhibitors against SARS-CoV-2 infection.

scholarly journals COVID-19 and androgen-targeted therapy for prostate cancer patients

2020 ◽  
Vol 27 (9) ◽  
pp. R281-R292 ◽  
Author(s):  
Neil A Bhowmick ◽  
Jillian Oft ◽  
Tanya Dorff ◽  
Sumanta Pal ◽  
Neeraj Agarwal ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Viral Entry ◽  
Host Cells ◽  
Angiotensin Converting Enzyme 2 ◽  
Cancer Management ◽  
Signaling Inhibitors ◽  
Androgen Regulation ◽  
Androgen Suppression ◽  
Transmembrane Serine Protease ◽  
Significant Disease

The current pandemic (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health challenge with active development of antiviral drugs and vaccines seeking to reduce its significant disease burden. Early reports have confirmed that transmembrane serine protease 2 (TMPRSS2) and angiotensin converting enzyme 2 (ACE2) are critical targets of SARS-CoV-2 that facilitate viral entry into host cells. TMPRSS2 and ACE2 are expressed in multiple human tissues beyond the lung including the testes where predisposition to SARS-CoV-2 infection may exist. TMPRSS2 is an androgen-responsive gene and its fusion represents one of the most frequent alterations in prostate cancer. Androgen suppression by androgen deprivation therapy and androgen receptor signaling inhibitors form the foundation of prostate cancer treatment. In this review, we highlight the growing evidence in support of androgen regulation of TMPRSS2 and ACE2 and the potential clinical implications of using androgen suppression to downregulate TMPRSS2 to target SARS-CoV-2. We also discuss the future directions and controversies that need to be addressed in order to establish the viability of targeting TMPRSS2 and/or ACE2 through androgen signaling regulation for COVID-19 treatment, particularly its relevance in the context of prostate cancer management.

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