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 Withanone from Withania somnifera May Inhibit Novel Coronavirus (COVID-19) Entry by Disrupting Interactions between Viral S-Protein Receptor Binding Domain and Host ACE2 Receptor

2020 ◽  
Author(s):  
Acharya Balkrishna ◽  
SUBARNA POKHREL ◽  
Jagdeep Singh ◽  
Anurag Varshney
Keyword(s):  
Receptor Binding ◽  
Withania Somnifera ◽  
Binding Domain ◽  
Host Cells ◽  
Receptor Binding Domain ◽  
Salt Bridges ◽  
Binding Interface ◽  
Electrostatic Component ◽  
Protein Receptor ◽  
First Choice

Abstract Background Newly emerged COVID-19 has been shown to engage the host cell ACE2 through its spike protein receptor binding domain (RBD). Here we show that natural phytochemical from a medicinal herb, Withania somnifera, have distinct effects on viral RBD and host ACE2 receptor complex. Methods We employed molecular docking to screen thousands of phytochemicals against the ACE2-RBD complex, performed molecular dynamics (MD) simulation, and estimated the electrostatic component of binding free energy, along with the computation of salt bridge electrostatics. Results We report that W. somnifera compound, Withanone, docked very well in the binding interface of AEC2-RBD complex, and was found to move slightly towards the interface centre on simulation. Withanone significantly decreased electrostatic component of binding free energies of ACE2-RBD complex. Two salt bridges were also identified at the interface; incorporation of Withanone destabilized these salt bridges and decreased their occupancies. We postulate, such an interruption of electrostatic interactions between the RBD and ACE2 would block or weaken COVID-19 entry and its subsequent infectivity. Conclusion Our data, for the first time, show that natural phytochemicals could well be the viable options for controlling COVID-19 entry into host cells, and W. somnifera may be the first choice of herbs in these directions to curb the COVID-19 infectivity.

scholarly journals The molecular basis for SARS-CoV-2 binding to dog ACE2

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zengyuan Zhang ◽  
Yanfang Zhang ◽  
Kefang Liu ◽  
Yan Li ◽  
Qiong Lu ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Molecular Basis ◽  
Domestic Animals ◽  
Receptor Binding Domain ◽  
Salt Bridges ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Interface ◽  
Protein Receptor ◽  
Contact Residues

AbstractSARS-CoV-2 can infect many domestic animals, including dogs. Herein, we show that dog angiotensin-converting enzyme 2 (dACE2) can bind to the SARS-CoV-2 spike (S) protein receptor binding domain (RBD), and that both pseudotyped and authentic SARS-CoV-2 can infect dACE2-expressing cells. We solved the crystal structure of RBD in complex with dACE2 and found that the total number of contact residues, contact atoms, hydrogen bonds and salt bridges at the binding interface in this complex are slightly fewer than those in the complex of the RBD and human ACE2 (hACE2). This result is consistent with the fact that the binding affinity of RBD to dACE2 is lower than that of hACE2. We further show that a few important mutations in the RBD binding interface play a pivotal role in the binding affinity of RBD to both dACE2 and hACE2. Our work reveals a molecular basis for cross-species transmission and potential animal spread of SARS-CoV-2, and provides new clues to block the potential transmission chains of this virus.

scholarly journals Cross-species recognition of SARS-CoV-2 to bat ACE2

2020 ◽  
Vol 118 (1) ◽  
pp. e2020216118
Author(s):  
Kefang Liu ◽  
Shuguang Tan ◽  
Sheng Niu ◽  
Jia Wang ◽  
Lili Wu ◽  
...  
Keyword(s):  
Binding Capacity ◽  
Species Recognition ◽  
Interaction Network ◽  
Binding Mode ◽  
Host Cells ◽  
Structural Basis ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Protein Receptor ◽  
Human Receptor

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a major threat to global health. Although varied SARS-CoV-2–related coronaviruses have been isolated from bats and SARS-CoV-2 may infect bat, the structural basis for SARS-CoV-2 to utilize the human receptor counterpart bat angiotensin-converting enzyme 2 (bACE2) for virus infection remains less understood. Here, we report that the SARS-CoV-2 spike protein receptor binding domain (RBD) could bind to bACE2 fromRhinolophus macrotis(bACE2-Rm) with substantially lower affinity compared with that to the human ACE2 (hACE2), and its infectivity to host cells expressing bACE2-Rm was confirmed with pseudotyped SARS-CoV-2 virus and SARS-CoV-2 wild virus. The structure of the SARS-CoV-2 RBD with the bACE2-Rm complex was determined, revealing a binding mode similar to that of hACE2. The analysis of binding details between SARS-CoV-2 RBD and bACE2-Rm revealed that the interacting network involving Y41 and E42 of bACE2-Rm showed substantial differences with that to hACE2. Bats have extensive species diversity and the residues for RBD binding in bACE2 receptor varied substantially among different bat species. Notably, the Y41H mutant, which exists in many bats, attenuates the binding capacity of bACE2-Rm, indicating the central roles of Y41 in the interaction network. These findings would benefit our understanding of the potential infection of SARS-CoV-2 in varied species of bats.

scholarly journals Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jinsung Yang ◽  
Simon J. L. Petitjean ◽  
Melanie Koehler ◽  
Qingrong Zhang ◽  
Andra C. Dumitru ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Living Cells ◽  
Host Cells ◽  
The Novel ◽  
Angiotensin Converting Enzyme 2 ◽  
Force Microscopy ◽  
Binding Interface ◽  
Atomic Force ◽  
Viral Glycoproteins ◽  
Novel Coronavirus

Abstract Study of the interactions established between the viral glycoproteins and their host receptors is of critical importance for a better understanding of virus entry into cells. The novel coronavirus SARS-CoV-2 entry into host cells is mediated by its spike glycoprotein (S-glycoprotein), and the angiotensin-converting enzyme 2 (ACE2) has been identified as a cellular receptor. Here, we use atomic force microscopy to investigate the mechanisms by which the S-glycoprotein binds to the ACE2 receptor. We demonstrate, both on model surfaces and on living cells, that the receptor binding domain (RBD) serves as the binding interface within the S-glycoprotein with the ACE2 receptor and extract the kinetic and thermodynamic properties of this binding pocket. Altogether, these results provide a picture of the established interaction on living cells. Finally, we test several binding inhibitor peptides targeting the virus early attachment stages, offering new perspectives in the treatment of the SARS-CoV-2 infection.

scholarly journals Possible Transmission Flow of SARS-CoV-2 Based on ACE2 Features

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5906
Author(s):  
Sk. Sarif Hassan ◽  
Shinjini Ghosh ◽  
Diksha Attrish ◽  
Pabitra Pal Choudhury ◽  
Alaa A. A. Aljabali ◽  
...  
Keyword(s):  
Amino Acids ◽  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Comprehensive Analysis ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Protein Receptor

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that is engendering the severe coronavirus disease 2019 (COVID-19) pandemic. The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 binds to the three sub-domains viz. amino acids (aa) 22–42, aa 79–84, and aa 330–393 of ACE2 on human cells to initiate entry. It was reported earlier that the receptor utilization capacity of ACE2 proteins from different species, such as cats, chimpanzees, dogs, and cattle, are different. A comprehensive analysis of ACE2 receptors of nineteen species was carried out in this study, and the findings propose a possible SARS-CoV-2 transmission flow across these nineteen species.

scholarly journals Structural Dissection of Viral Spike-Protein Binding of SARS-CoV-2 and SARS-CoV-1 to the Human Angiotensin-Converting Enzyme 2 (ACE2) as Cellular Receptor

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1038
Author(s):  
Deborah Giordano ◽  
Luigi De Masi ◽  
Maria Antonia Argenio ◽  
Angelo Facchiano
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico Analysis ◽  
Host Cells ◽  
Spike Protein ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
The World ◽  
Silico Analysis

An outbreak by a new severe acute respiratory syndrome betacoronavirus (SARS-CoV-2) has spread CoronaVirus Disease 2019 (COVID-19) all over the world. Immediately, following studies have confirmed the human Angiotensin-Converting Enzyme 2 (ACE2) as a cellular receptor of viral Spike-Protein (Sp) that mediates the CoV-2 invasion into the pulmonary host cells. Here, we compared the molecular interactions of the viral Sp from previous SARS-CoV-1 of 2002 and SARS-CoV-2 with the host ACE2 protein by in silico analysis of the available experimental structures of Sp-ACE2 complexes. The K417 amino acid residue, located in the region of Sp Receptor-Binding Domain (RBD) of the new coronavirus SARS-CoV-2, showed to have a key role for the binding to the ACE2 N-terminal region. The R426 residue of SARS-CoV-1 Sp-RBD also plays a key role, although by interacting with the central region of the ACE2 sequence. Therefore, our study evidenced peculiarities in the interactions of the two Sp-ACE2 complexes. Our outcomes were consistent with previously reported mutagenesis studies on SARS-CoV-1 and support the idea that a new and different RBD was acquired by SARS-CoV-2. These results have interesting implications and suggest further investigations.

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 Computational Hot-Spot Analysis of the SARS-CoV-2 Receptor Binding Domain / ACE2 Complex

2020 ◽  
Author(s):  
Pedro A. Rosario ◽  
Brian R. McNaughton
Keyword(s):  
Receptor Binding ◽  
Hot Spot ◽  
Initial Step ◽  
Positive Control ◽  
Binding Domain ◽  
Host Cells ◽  
Receptor Binding Domain ◽  
Alanine Scanning Mutagenesis ◽  
Binding Interface ◽  
Computational Alanine Scanning

AbstractInfection and replication of SARS CoV-2 (the virus that causes COVID-19) requires entry to the interior of host cells. In humans, a Protein-Protein Interaction (PPI) between the SARS CoV-2 Receptor-Binding Domain (RBD) and the extracellular peptidase domain of ACE2, on the surface of cells in the lower respiratory tract, is an initial step in the entry pathway. Inhibition of the SARS CoV-2 RBD / ACE2 PPI is currently being evaluated as a target for therapeutic and/or prophylactic intervention. However, relatively little is known about the molecular underpinnings of this complex. Employing multiple computational platforms, we predicted ‘hot-spot’ residues in a positive control PPI (PMI / MDM2) and the CoV-2 RBD/ACE2 complex. Computational alanine scanning mutagenesis was performed to predict changes in Gibbs’ free energy that are associated with mutating residues at the positive control (PMI/MDM2) or SARS RBD/ACE2 binding interface to alanine. Additionally, we used the Adaptive Poisson-Boltzmann Solver to calculate macromolecular electrostatic surfaces at the interface of the positive control PPI and SARS CoV-2 / ACE2 PPI. Collectively, this study illuminates predicted hot-spot residues, and clusters, at the SARS CoV-2 RBD / ACE2 binding interface, potentially guiding the development of reagents capable of disrupting this complex and halting COVID-19.

scholarly journals Millisecond-scale molecular dynamics simulation of spike RBD structure reveals evolutionary adaption of SARS-CoV-2 to stably bind ACE2

2020 ◽  
Author(s):  
Gard Nelson ◽  
Oleksandr Buzko ◽  
Aaron Bassett ◽  
Patricia R Spilman ◽  
Kayvan Niazi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Receptor Binding Domain ◽  
Binding Region ◽  
Angiotensin Converting Enzyme 2 ◽  
Molecular Binding ◽  
Relative Affinity ◽  
Therapeutic Development

The Receptor Binding Domain (RBD) of the SARS-CoV-2 surface spike (S) protein interacts with host angiotensin converting enzyme 2 (ACE2) to gain entry to host cells and initiate infection 1-3. Detailed, accurate understanding of key interactions between S RBD and ACE2 provides critical information that may be leveraged in the development of strategies for the prevention and treatment of COVID-19. Utilizing the published sequences and cryo-EM structures of both the viral S RBD and ACE2 4,5, we performed in silico molecular dynamics (MD) simulations of free S RBD and of its interaction with ACE2 over the exceptionally long durations of 2.9 and 2 milliseconds, respectively, to elucidate the nature and relative affinity of S RBD surface residues for the ACE2 binding region. Our findings reveal that free S RBD has assumed an optimized ACE2 binding-ready conformation, incurring little entropic penalty for binding, an evolutionary adaptation that contributes to its high affinity for the receptor 6. We further identified high probability molecular binding interactions that inform both vaccine design and therapeutic development, which may include recombinant ACE2-based spike decoys 7 and/or allosteric S RBD-ACE2 binding inhibitors 8,9 to prevent or arrest infection and thus disease.

Sign in / Sign up

Export Citation Format

Share Document