scholarly journals Structural Analysis of the Novel Variants of SARS-CoV-2 and Forecasting in North America

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 930
Author(s):  
Elena Quinonez ◽  
Majid Vahed ◽  
Abdolrazagh Hashemi Shahraki ◽  
Mehdi Mirsaeidi
Keyword(s):  
North America ◽  
Angiotensin Converting Enzyme ◽  
Neutralizing Antibodies ◽  
Herd Immunity ◽  
Neutralizing Antibody ◽  
The Novel ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Global Database ◽  
Novel Variants

Background: little is known about the forecasting of new variants of SARS-COV-2 in North America and the interaction of variants with vaccine-derived neutralizing antibodies. Methods: the affinity scores of the spike receptor-binding domain (S-RBD) of B.1.1.7, B. 1.351, B.1.617, and P.1 variants in interaction with the neutralizing antibody (CV30 isolated from a patient), and human angiotensin-converting enzyme 2 (hACE2) receptor were predicted using the template-based computational modeling. From the Nextstrain global database, we identified prevalent mutations of S-RBD of SARS-CoV-2 from December 2019 to April 2021. Pre- and post-vaccination time series forecasting models were developed based on the prediction of neutralizing antibody affinity scores for S-RBD of the variants. Results: the proportion of the B.1.1.7 variant in North America is growing rapidly, but the rate will reduce due to high affinity (~90%) to the neutralizing antibody once herd immunity is reached. Currently, the rates of isolation of B. 1.351, B.1.617, and P.1 variants are slowly increasing in North America. Herd immunity is able to relatively control these variants due to their low affinity (~70%) to the neutralizing antibody. The S-RBD of B.1.617 has a 110% increased affinity score to the human angiotensin-converting enzyme 2 (hACE2) in comparison to the wild-type structure, making it highly infectious. Conclusion: The newly emerged B.1.351, B.1.617, and P.1 variants escape from vaccine-induced neutralizing immunity and continue circulating in North America in post- herd immunity era. Our study strongly suggests that a third dose of vaccine is urgently needed to cover novel variants with affinity scores (equal or less than 70%) to eliminate developing viral mutations and reduce transmission rates.

scholarly journals Mutations in two SARS-CoV-2 variants of concern reflect two distinct strategies of antibody escape

2021 ◽  
Author(s):  
Sebastian Fiedler ◽  
Viola Denninger ◽  
Alexey S. Morgunov ◽  
Alison Ilsley ◽  
Roland Worth ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Cell Receptor ◽  
Converting Enzyme ◽  
Wild Type ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Domains ◽  
Host Cell Receptor

Understanding the factors that contribute to antibody escape of SARS-CoV-2 and its variants is key for the development of drugs and vaccines that provide broad protection against a variety of virus variants. Using microfluidic diffusional sizing, we determined the dissociation constant ((KD)) for the interaction between receptor binding domains (RBDs) of SARS-CoV-2 in its original version (WT) as well as alpha and beta variants with the host-cell receptor angiotensin converting enzyme 2 (ACE2). For RBD-alpha, the ACE2-binding affinity was increased by a factor of ten when compared with RBD-WT, while ACE2-binding of RBD-beta was largely unaffected. However, when challenged with a neutralizing antibody that binds to both RBD-WT and RBD-alpha with low nanomolar (KD) values, RBD-beta displayed no binding, suggesting a substantial epitope change. In SARS-CoV-2 convalescent sera, RBD-binding antibodies showed low nanomolar affinities to both wild-type and variant RBD proteins—strikingly, the concentration of antibodies binding to RBD-beta was half that of RBD-WT and RBD-alpha, again indicating considerable epitope changes in the beta variant. Our data therefore suggests that one factor contributing to the higher transmissibility and antibody evasion of SARS-CoV-2 alpha and beta is a larger fraction of viruses that can form a complex with ACE2. However, the two variants employ different mechanisms to achieve this goal. While SARS-CoV-2 alpha RBD binds with greater affinity to ACE2 and is thus more difficult to displace from the receptor by neutralizing antibodies, RBD-beta is less accessible to antibodies due to epitope changes which increases the chances of ACE2-binding and infection.

scholarly journals ACE2 Nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Sally Badawi ◽  
Bassam R. Ali
Keyword(s):  
Cell Surface ◽  
Angiotensin Converting Enzyme ◽  
The Novel ◽  
Converting Enzyme ◽  
Post Translational Modifications ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Attachment ◽  
Novel Coronavirus ◽  
Effective Medication ◽  
Potential Use

AbstractWith the emergence of the novel coronavirus SARS-CoV-2 since December 2019, more than 65 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases, leading to over 1.5 million deaths globally. Despite the collaborative and concerted research efforts that have been made, no effective medication for COVID-19 (coronavirus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in the human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2–based therapeutic strategies have aimed to tackle the virus through the use of angiotensin-converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2, which does not directly aim to reduce its membrane availability. However, through this review, we present a different perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, and shedding and cellular trafficking pathways including the internalization are not well elucidated in literature. Therefore, we hereby present an overview of the fate of newly synthesized ACE2, its post translational modifications, and what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Moreover, an extensive understanding of these processes is necessarily required to evaluate the potential use of ACE2 as a credible therapeutic target.

scholarly journals A time series forecasting of the proportion of SARS-CoV-2 N501Y lineage in North America

2021 ◽  
Author(s):  
Elena Quinonez ◽  
Majid Vahed ◽  
Abdolrazagh Hashemi Shahraki ◽  
Mehdi Mirsaeidi
Keyword(s):  
Time Series ◽  
North America ◽  
South African ◽  
Neutralizing Antibodies ◽  
Genomic Sequence ◽  
Natural Infection ◽  
Rapid Evolution ◽  
Neutralizing Antibody ◽  
Time Series Forecasting ◽  
Global Database

Introduction: The outbreak of pneumonia known as SARS-COV-2 and newly-emerging South African (B.1.351), the United Kingdom (B.1.1.7) and Brazil (P.1) variants have led to a more infectious virus and potentially more substantial loss of neutralizing activity by natural infection or vaccine-elicited antibodies. Methods: We identified prevalent mutations using the spike receptor-binding domain (S-RBD) of SARS-CoV-2 deposited in the Nextstrain global database and comparing them to the Wuhan-Hu-1/2019 genomic sequence as a reference. Then we calculated the percentages of mutant genomes from the total regional subsample isolates from December 2019 to the end of January 2021. We developed two separate time series forecasting models for the SARS-CoV-2 B.1.1.7 variant. The computational model used the structure of the S-RBD to examine its interactions with the neutralizing antibody, named CV30 (isolated from a patient), and human angiotensin-converting enzyme 2 (hACE-2), based on a hybrid algorithm of template-based modeling to predict the affinity of S protein to the neutralizing antibodies and hACE-2 receptor. Results: The proportion of the B.1.1.7 strain in North America is growing fast. From these computations, it seems that the S-RBD and hACE-2 proteins are less favorable for the South African strain (K417N, E484K, and N501Y) as compared to the wild type structure and more favorable for B.1.1.7 and P.1 variants. In the present of crystallized CV30 neutralizing antibodies, docking scores suggest antibodies can be partially neutralize the B.1.1.7 variant, and, less efficiently, the B.1.351 and P.1 variants. Conclusion: The rapid evolution of SARS-CoV-2 has the potential to allow the newly-emerged B.1.351, and P.1 variants to escape from natural or vaccine-induced neutralizing immunity and viral spreading.

scholarly journals Amino acids 484 and 494 of SARS-CoV-2 spike are hotspots of immune evasion affecting antibody but not ACE2 binding

2021 ◽  
Author(s):  
Marta Alenquer ◽  
Filipe Ferreira ◽  
Diana Lousa ◽  
Mariana Valério ◽  
Mónica Medina-Lopes ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Angiotensin Converting Enzyme ◽  
Immune Evasion ◽  
Neutralizing Antibodies ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Antibody Neutralization ◽  
Angiotensin Converting Enzyme 2 ◽  
The Core

AbstractUnderstanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike and, predominantly, of its receptor-binding-domain (RBD). Mutations in spike impacting antibody or ACE2 binding are known, but the effect of mutation synergy is less explored. We engineered 22 spike-pseudotyped lentiviruses containing individual and combined mutations, and confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations. In silico analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent sera. This amino acid emerges as an additional hotspot for immune evasion and a target for therapies, vaccines and diagnostics.One-Sentence SummaryAmino acids in SARS-CoV-2 spike protein implicated in immune evasion are biased for binding to neutralizing antibodies but dispensable for binding the host receptor angiotensin-converting enzyme 2.

scholarly journals Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Keiji Kuba ◽  
Tomokazu Yamaguchi ◽  
Josef M. Penninger
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Neutralizing Antibodies ◽  
Cell Entry ◽  
Converting Enzyme ◽  
Sars Coronavirus ◽  
Angiotensin Converting Enzyme 2 ◽  
Infected People ◽  
Critical Attention ◽  
Novel Coronavirus

Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS coronavirus. Despite many similarities to SARS coronavirus, SARS-CoV-2 exhibits a higher affinity to ACE2 and shows higher infectivity and transmissibility, resulting in explosive increase of infected people and COVID-19 patients. Emergence of the variants harboring mutations in the receptor-binding domain of the Spike protein has drawn critical attention to the interaction between ACE2 and Spike and the efficacies of vaccines and neutralizing antibodies. ACE2 is a carboxypeptidase which degrades angiotensin II, B1-bradykinin, or apelin, and thereby is a critical regulator of cardiovascular physiology and pathology. In addition, the enzymatic activity of ACE2 is protective against acute respiratory distress syndrome (ARDS) caused by viral and non-viral pneumonias, aspiration, or sepsis. Upon infection, both SARS-CoV-2 and SARS coronaviruses downregulates ACE2 expression, likely associated with the pathogenesis of ARDS. Thus, ACE2 is not only the SARS-CoV-2 receptor but might also play an important role in multiple aspects of COVID-19 pathogenesis and possibly post-COVID-19 syndromes. Soluble forms of recombinant ACE2 are currently utilized as a pan-variant decoy to neutralize SARS-CoV-2 and a supplementation of ACE2 carboxypeptidase activity. Here, we review the role of ACE2 in the pathology of ARDS in COVID-19 and the potential application of recombinant ACE2 protein for treating COVID-19.

scholarly journals An Ultrapotent Neutralizing Bispecific Antibody with Broad Spectrum Against SARS-CoV-2 Variants

2021 ◽  
Author(s):  
Hui Zhang ◽  
Haohui Huang ◽  
Rong Li ◽  
Lu Zhang ◽  
Zhiwei Wang ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Bispecific Antibody ◽  
Herd Immunity ◽  
Therapeutic Effects ◽  
Bodyweight Loss ◽  
Receptor Binding Domain ◽  
Single Administration ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
High Affinity

Abstract Some variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are threatening our global efforts of herd immunity, novel and more efficacious agents are urgently needed. We have developed a bispecific antibody, 2022, which bonds with high affinity to two non-overlapping epitopes on the receptor-binding domain (RBD) simultaneously, blocks the binding of RBD to human angiotensin-converting enzyme 2 (ACE2), and potently neutralizes SARS-CoV-2 and all of the variants tested, including variants carrying mutations known to resist neutralizing antibodies approved under Emergency Use Authorization (EUA) and reduce the efficacy of existing vaccines. In a mouse model of SARS-CoV-2, 2022 showed strong prophylactic and therapeutic effects. A single administration of 2022 completely protected all mice from bodyweight loss, as compared with up to 20% loss of bodyweight in placebo treated mice, reduced the lung viral titers to undetectable in all mice treated with 2022 either prophylactically or therapeutically, as compared with around 1X105 pfu/g lung tissue in placebo treated mice. In summary, bispecific antibody 2022 showed potent binding and neutralizing activity across a variety of SARS-CoV-2 variants and could be an attractive weapon to combat the ongoing waves of the COVID-19 pandemic.

scholarly journals ACE2 Nascence, Trafficking and SARS-CoV-2 Pathogenesis: The Saga Continues

2020 ◽  
Author(s):  
Sally Badawi ◽  
Bassam Ali
Keyword(s):  
Cell Surface ◽  
Angiotensin Converting Enzyme ◽  
Virus Disease ◽  
The Novel ◽  
Converting Enzyme ◽  
Post Translational Modifications ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Attachment ◽  
Corona Virus ◽  
Potential Use

With the emergence of the novel corona virus SARS-CoV-2 since December 2019, more than 43 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases leading to over 1 million deaths globally. Despite the collaborative and concerted research efforts that has been made, no effective treatment for COVID-19 (corona virus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2–based therapeutic strategies have aimed to achieve this through the use of angiotensin converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2. However, through this review, we present another perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, shedding and its cellular trafficking pathways including internalization are not well elucidated. Therefore, hereby we present an overview on the fate of newly synthesized ACE2, its post translational modifications, what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Extensive understanding of these processes is necessary to evaluate the potential use of ACE2 as a credible therapeutic target.

scholarly journals Acute Pancreatitis in a Patient With COVID-19 After the Resolution of Respiratory Symptoms

2021 ◽  
Vol 9 ◽  
pp. 232470962110247
Author(s):  
Hafiz Muhammad Abrar Jeelani ◽  
Muhammad Mubbashir Sheikh ◽  
Shirly Susan Samuel ◽  
Yetunde Bernice Omotosho ◽  
Artem Sharko ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Angiotensin Converting Enzyme ◽  
Respiratory Symptoms ◽  
Epigastric Pain ◽  
The Novel ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Novel Coronavirus

The gastrointestinal (GI) involvement, including acute pancreatitis (AP) from the novel coronavirus disease-2019 (COVID-19), is increasingly being reported. Recent evidence suggests that the pathogenesis of COVID-19 is mediated by the angiotensin-converting enzyme 2 (ACE-2) receptors and transmembrane protease serine 2 (TMPRSS2) for “priming,” which is highly expressed in the pancreas. To our knowledge, there is no other reported case of AP associated with COVID-19 after the respiratory symptoms are resolved. In this article, we present a patient with COVID-19, who came with intractable epigastric pain and resolved respiratory symptoms. A diagnosis of AP complicated with COVID-19 was made after laboratory and imaging workup, which was successfully managed conservatively.

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