scholarly journals A monoclonal antibody that neutralizes SARS-CoV-2 variants, SARS-CoV, and other sarbecoviruses

2021 ◽  
Author(s):  
Pengfei Wang ◽  
Ryan G Casner ◽  
Manoj S Nair ◽  
Jian Yu ◽  
Yicheng Guo ◽  
...  
Keyword(s):  
Drug Candidate ◽  
Receptor Binding Domain ◽  
Highly Pathogenic ◽  
Angiotensin Converting Enzyme 2 ◽  
Promising Target ◽  
Prevention And Treatment ◽  
Human Coronaviruses ◽  
Strategic Reserve ◽  
Conserved Epitope

The repeated emergence of highly pathogenic human coronaviruses as well as their evolving variants highlight the need to develop potent and broad-spectrum antiviral therapeutics and vaccines. By screening monoclonal antibodies (mAbs) isolated from COVID-19-convalescent patients, we found one mAb, 2-36, with cross-neutralizing activity against SARS-CoV. We solved the cryo-EM structure of 2-36 in complex with SARS-CoV-2 or SARS-CoV spike, revealing a highly conserved epitope in the receptor-binding domain (RBD). Antibody 2-36 neutralized not only all current circulating SARS-CoV-2 variants and SARS-COV, but also a panel of bat and pangolin sarbecoviruses that can use human angiotensin-converting enzyme 2 (ACE2) as a receptor. We selected 2-36-escape viruses in vitro and confirmed that K378T in SARS-CoV-2 RBD led to viral resistance. Taken together, 2-36 represents a strategic reserve drug candidate for the prevention and treatment of possible diseases caused by pre-emergent SARS-related coronaviruses. Its epitope defines a promising target for the development of a pan-sarbecovirus vaccine.

scholarly journals Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation

2020 ◽  
Author(s):  
Ting Gao ◽  
Mingdong Hu ◽  
Xiaopeng Zhang ◽  
Hongzhen Li ◽  
Lin Zhu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Lung Injury ◽  
Complement Activation ◽  
Suppressive Effect ◽  
Lectin Pathway ◽  
Highly Pathogenic ◽  
N Protein ◽  
Promising Target

AbstractAn excessive immune response contributes to SARS-CoV, MERS-CoV and SARS-CoV-2 pathogenesis and lethality, but the mechanism remains unclear. In this study, the N proteins of SARS-CoV, MERS-CoV and SARS-CoV-2 were found to bind to MASP-2, the key serine protease in the lectin pathway of complement activation, resulting in aberrant complement activation and aggravated inflammatory lung injury. Either blocking the N protein:MASP-2 interaction or suppressing complement activation can significantly alleviate N protein-induced complement hyper-activation and lung injury in vitro and in vivo. Complement hyper-activation was also observed in COVID-19 patients, and a promising suppressive effect was observed when the deteriorating patients were treated with anti-C5a monoclonal antibody. Complement suppression may represent a common therapeutic approach for pneumonia induced by these highly pathogenic coronaviruses.One Sentence SummaryThe lectin pathway of complement activation is a promising target for the treatment of highly pathogenic coronavirus induced pneumonia.

scholarly journals Identification of a conserved neutralizing epitope present on spike proteins from all highly pathogenic coronaviruses

2021 ◽  
Author(s):  
Yimin Huang ◽  
Annalee W. Nguyen ◽  
Ching-Lin Hsieh ◽  
Rui Silva ◽  
Oladimeji S. Olaluwoye ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Conformational Epitope ◽  
Neutralizing Epitope ◽  
Highly Pathogenic ◽  
Exchange Mass Spectrometry ◽  
Global Pandemic ◽  
Hydrogen Deuterium ◽  
Deuterium Exchange Mass Spectrometry ◽  
Human Coronaviruses

ABSTRACTThree pathogenic human coronaviruses have emerged, with SARS-CoV-2 causing a global pandemic. While therapeutic antibodies targeting the SARS-2 spike currently focus on the poorly conserved receptor-binding domain, targeting essential neutralizing epitopes on the more conserved S2 domain may provide broader protection. We report three antibodies, binding epitopes conserved on the pre-fusion MERS, SARS-1 and SARS-2 spike S2 domains. Antibody 3A3 binds a conformational epitope with ~2.5 nM affinity and neutralizes in in vitro SARS-2 cell fusion and pseudovirus assays. Hydrogen-deuterium exchange mass spectrometry identified residues 980-1006 in the flexible hinge region at the S2 apex as the 3A3 epitope, consistent with binding to natural and engineered spike variants. This location at the spike trimer interface suggests 3A3 prevents the S2 conformational rearrangements required for virus-host cell fusion. This work defines a highly conserved vulnerable site on the SARS-2 S2 domain and may help guide the design of pan-protective spike immunogens.TEASERA conserved, neutralizing epitope in the S2 domain of coronavirus spike was identified as a target for pan-coronavirus therapy and vaccination.

scholarly journals HTCC as a Polymeric Inhibitor of SARS-CoV-2 and MERS-CoV

2020 ◽  
Author(s):  
Aleksandra Milewska ◽  
Ying Chi ◽  
Artur Szczepanski ◽  
Emilia Barreto-Duran ◽  
Agnieszka Dabrowska ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Ex Vivo ◽  
Multiorgan Failure ◽  
Highly Pathogenic ◽  
Modified Chitosan ◽  
Human Airway Epithelium ◽  
Human Coronaviruses ◽  
Novel Coronavirus ◽  
Global And Local

Among seven coronaviruses that infect humans, three (SARS-CoV, MERS-CoV, and the newly identified SARS-CoV-2) are associated with a severe, life-threatening respiratory infection and multiorgan failure. We previously proposed that the cationically modified chitosan, N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC) is a potent inhibitor of HCoV-NL63. Next, we demonstrated the broad-spectrum antiviral activity of the compound, as it inhibited all low pathogenic human coronaviruses (HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1). Here, using in vitro and ex vivo model of human airway epithelium, we show that HTCC effectively blocks MERS-CoV and SARS-CoV-2 infection. We also confirmed the mechanism of action for these two viruses, showing that the polymer blocks the virus entry to the host cell by interaction with the S protein. IMPORTANCE The beginning of 2020 brought us information about the novel coronavirus emerging in China. Rapid research resulted in the characterization of the pathogen, which appeared to be a member of the SARS-like cluster, commonly seen in bats. Despite the global and local efforts, the virus escaped the health care measures and rapidly spread in China and later globally, officially causing a pandemic and global crisis in March 2020. At present, different scenarios are being written to contain the virus, but the development of novel anticoronavirals for all highly pathogenic coronaviruses remains the major challenge. Here, we describe the antiviral activity of previously developed by us HTCC compound, which may be used as a potential inhibitor of currently circulating highly pathogenic coronaviruses – SARS-CoV-2 and MERS-CoV.

scholarly journals Neutralizing antibodies for the prevention and treatment of COVID-19

2021 ◽  
Author(s):  
Lanying Du ◽  
Yang Yang ◽  
Xiujuan Zhang
Keyword(s):  
Neutralizing Antibodies ◽  
Virus Entry ◽  
Infection Process ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Prevention And Treatment ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

AbstractSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initiates the infection process by binding to the viral cellular receptor angiotensin-converting enzyme 2 through the receptor-binding domain (RBD) in the S1 subunit of the viral spike (S) protein. This event is followed by virus–cell membrane fusion mediated by the S2 subunit, which allows virus entry into the host cell. Therefore, the SARS-CoV-2 S protein is a key therapeutic target, and prevention and treatment of coronavirus disease 2019 (COVID-19) have focused on the development of neutralizing monoclonal antibodies (nAbs) that target this protein. In this review, we summarize the nAbs targeting SARS-CoV-2 proteins that have been developed to date, with a focus on the N-terminal domain and RBD of the S protein. We also describe the roles that binding affinity, neutralizing activity, and protection provided by these nAbs play in the prevention and treatment of COVID-19 and discuss the potential to improve nAb efficiency against multiple SARS-CoV-2 variants. This review provides important information for the development of effective nAbs with broad-spectrum activity against current and future SARS-CoV-2 strains.

scholarly journals Dalbavancin binds ACE2 to block its interaction with SARS-CoV-2 spike protein and is effective in inhibiting SARS-CoV-2 infection in animal models

Cell Research ◽  
2020 ◽  
Vol 31 (1) ◽  
pp. 17-24 ◽  
Author(s):  
Gan Wang ◽  
Meng-Li Yang ◽  
Zi-Lei Duan ◽  
Feng-Liang Liu ◽  
Lin Jin ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Spike Protein ◽  
Drug Candidate ◽  
Peptide Drug ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
High Affinity ◽  
Plasma Half Life

AbstractInfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC50 of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8–10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.

scholarly journals An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shiho Tanaka ◽  
Gard Nelson ◽  
C. Anders Olson ◽  
Oleksandr Buzko ◽  
Wendy Higashide ◽  
...  
Keyword(s):  
Md Simulation ◽  
Therapeutic Option ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
High Likelihood ◽  
Wild Type ◽  
Angiotensin Converting Enzyme 2 ◽  
High Affinity ◽  
Sustained Efficacy

AbstractThe SARS-CoV-2 variants replacing the first wave strain pose an increased threat by their potential ability to escape pre-existing humoral protection. An angiotensin converting enzyme 2 (ACE2) decoy that competes with endogenous ACE2 for binding of the SARS-CoV-2 spike receptor binding domain (S RBD) and inhibits infection may offer a therapeutic option with sustained efficacy against variants. Here, we used Molecular Dynamics (MD) simulation to predict ACE2 sequence substitutions that might increase its affinity for S RBD and screened candidate ACE2 decoys in vitro. The lead ACE2(T27Y/H34A)-IgG1FC fusion protein with enhanced S RBD affinity shows greater live SARS-CoV-2 virus neutralization capability than wild type ACE2. MD simulation was used to predict the effects of S RBD variant mutations on decoy affinity that was then confirmed by testing of an ACE2 Triple Decoy that included an additional enzyme activity-deactivating H374N substitution against mutated S RBD. The ACE2 Triple Decoy maintains high affinity for mutated S RBD, displays enhanced affinity for S RBD N501Y or L452R, and has the highest affinity for S RBD with both E484K and N501Y mutations, making it a viable therapeutic option for the prevention or treatment of SARS-CoV-2 infection with a high likelihood of efficacy against variants.

scholarly journals A Bioluminescent Biosensor for Quantifying the Interaction of SARS-CoV-2 and Its Receptor ACE2 in Cells and In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1055
Author(s):  
Xiaolong Yang ◽  
Lidong Liu ◽  
Yawei Hao ◽  
Eva So ◽  
Sahar Sarmasti Emami ◽  
...  
Keyword(s):  
Small Molecules ◽  
Living Cells ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Discovery Process ◽  
Drug Discovery Process ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Interactions

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is currently spreading and mutating with increasing speed worldwide. Therefore, there is an urgent need for a simple, sensitive, and high-throughput (HTP) assay to quantify virus–host interactions in order to quickly evaluate the infectious ability of mutant viruses and to develop or validate virus-inhibiting drugs. Here, we developed an ultrasensitive bioluminescent biosensor to evaluate virus–cell interactions by quantifying the interaction between the SARS-CoV-2 receptor binding domain (RBD) and its cellular receptor angiotensin-converting enzyme 2 (ACE2) both in living cells and in vitro. We have successfully used this novel biosensor to analyze SARS-CoV-2 RBD mutants and evaluated candidate small molecules (SMs), antibodies, and peptides that may block RBD:ACE2 interaction. This simple, rapid, and HTP biosensor tool will significantly expedite the detection of viral mutants and the anti-COVID-19 drug discovery process.

scholarly journals A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2)

2021 ◽  
Vol 14 (10) ◽  
pp. 954
Author(s):  
Paolo Coghi ◽  
Li Jun Yang ◽  
Jerome P. L. Ng ◽  
Richard K. Haynes ◽  
Maurizio Memo ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Cell Invasion ◽  
Binding Domain ◽  
Spike Protein ◽  
Interaction Patterns ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2

Host cell invasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, computational and experimental techniques were combined to screen antimalarial compounds from different chemical classes, with the aim of identifying small molecules interfering with the RBD-ACE2 interaction and, consequently, with cell invasion. Docking studies showed that the compounds interfere with the same region of the RBD, but different interaction patterns were noted for ACE2. Virtual screening indicated pyronaridine as the most promising RBD and ACE2 ligand, and molecular dynamics simulations confirmed the stability of the predicted complex with the RBD. Bio-layer interferometry showed that artemisone and methylene blue have a strong binding affinity for RBD (KD = 0.363 and 0.226 μM). Pyronaridine also binds RBD and ACE2 in vitro (KD = 56.8 and 51.3 μM). Overall, these three compounds inhibit the binding of RBD to ACE2 in the μM range, supporting the in silico data.

scholarly journals A potently neutralizing anti-SARS-CoV-2 antibody inhibits variants of concern by binding a highly conserved epitope

2021 ◽  
Author(s):  
Laura A. VanBlargan ◽  
Lucas J. Adams ◽  
Zhuoming Liu ◽  
Rita E. Chen ◽  
Pavlo Gilchuk ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Spike Protein ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Virus Attachment ◽  
Inhibitory Antibodies ◽  
Conserved Epitope

SUMMARYWith the emergence of SARS-CoV-2 variants with increased transmissibility and potential resistance, antibodies and vaccines with broadly inhibitory activity are needed. Here we developed a panel of neutralizing anti-SARS-CoV-2 mAbs that bind the receptor binding domain of the spike protein at distinct epitopes and block virus attachment to cells and its receptor, human angiotensin converting enzyme-2 (hACE2). While several potently neutralizing mAbs protected K18-hACE2 transgenic mice against infection caused by historical SARS-CoV-2 strains, others induced escape variantsin vivoand lost activity against emerging strains. We identified one mAb, SARS2-38, that potently neutralizes all SARS-CoV-2 variants of concern tested and protects mice against challenge by multiple SARS-CoV-2 strains. Structural analysis showed that SARS2-38 engages a conserved epitope proximal to the receptor binding motif. Thus, treatment with or induction of inhibitory antibodies that bind conserved spike epitopes may limit the loss of potency of therapies or vaccines against emerging SARS-CoV-2 variants.

scholarly journals Therapeutic efficacy of CT-P59 against P.1 variant of SARS-CoV-2

2021 ◽  
Author(s):  
Soo-Young Lee ◽  
Dong-Kyun Ryu ◽  
bobin Kang ◽  
Hanmi Noh ◽  
Jongin Kim ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Survival Rates ◽  
In Vitro Assays ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Loads ◽  
Weight Losses ◽  
Animal Tests

P.1. or gamma variant also known as the Brazil variant, is one of the variants of concern (VOC) which appears to have high transmissibility and mortality. To explore the potency of the CT-P59 monoclonal antibody against P.1 variant, we tried to conduct binding affinity, in vitro neutralization, and in vivo animal tests. In in vitro assays revealed that CT-P59 is able to neutralize P.1 variant in spite of reduction in its binding affinity against a RBD (receptor binding domain) mutant protein including K417T/E484K/N501Y and neutralizing activity against P.1 pseudoviruses and live viruses. In contrast, in vivo hACE2 (human angiotensin-converting enzyme 2)-expressing TG (transgenic) mouse challenge experiment demonstrated that a clinically relevant or lower dosages of CT-P59 is capable of lowering viral loads in the respiratory tract and alleviates symptoms such as body weight losses and survival rates. Therefore, a clinical dosage of CT-P59 could compensate for reduced in vitro antiviral activity in P.1-infected mice, implying that CT-P59 has therapeutic potency for COVID-19 patients infected with P.1 variant.

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