The potential of melatonin in the prevention and attenuation of oxidative hemolysis and myocardial injury from cd147 SARS-CoV-2 spike protein receptor binding

2020 ◽  
Vol 3 (3) ◽  
pp. 380-416
Author(s):  
Doris Loh
Keyword(s):  
Receptor Binding ◽  
Myocardial Injury ◽  
Antioxidant Properties ◽  
Organ Damage ◽  
Multiple Organ ◽  
Full Potential ◽  
Oxidative Hemolysis ◽  
S Protein ◽  
Protein Receptor ◽  
Refractory Hypoxemia

     The rapid escalation of pandemic health threats associated with the novel, pathogenic SARS-CoV-2 coronavirus poses unprecedented challenges as proven effective vaccines and drugs have yet to be produced. Refractory hypoxemia and myocardial injury have been observed as two of the major causes of fatality in COVID-19 patients. SARS-CoV-2 spike (S) protein binding to broadly expressed CD147 receptors on erythrocytes causes oxidative hemolysis that may result in refractory hypoxemia and myocardial injury. Both of these life-threatening conditions are further exacerbated by imbalance in ACE2 from spike (S) protein receptor binding. Dysregulation in the CD147-cyclophilin A signaling pathway, together with altered calcium signaling from SARS-CoV-2 ion channel activities, may contribute to hypercoagulation, thrombosis, and cardiac remodeling resulting in heart failure. Melatonin is an ancient pleiotropic molecule with recognized antioxidant properties that is essential for the protection of erythrocytes from oxidative hemolysis. Found in erythrocytes, melatonin can reverse hemolytic anemia, normalize heme synthesis, restore lymphocytes and platelet counts, and reduce vessel permeability during an acute hemolytic crisis by maintaining intracellular calcium homeostasis and reduction of oxidative stress. In acute hypoxic conditions, melatonin is cardioprotective via blunting of cardiopulmonary response to hypoxia and suppressing hypoxia pathways. Melatonin normalizes endothelial-dependent nitric oxide production to prevent multiple organ damage from hypercoagulability, thrombosis, and hypertension associated with oxidative hemolysis and ACE2 deficiency, protecting cardiomyocytes from hypertrophy. This review discusses the full potential of melatonin as a safe and effective therapeutic intervention for the prevention and attenuation of hemoglobinopathies, refractory hypoxemia and myocardial injury during critical COVID-19 infections. 

scholarly journals SARS-CoV-2 convergent evolution as a guide to explore adaptive advantage

2021 ◽  
Author(s):  
Jiri Zahradnik ◽  
Jaroslav Nunvar ◽  
Gideon Schreiber
Keyword(s):  
Receptor Binding ◽  
Convergent Evolution ◽  
Great Majority ◽  
Viral Population ◽  
Binding Motif ◽  
Furin Cleavage ◽  
S Protein ◽  
Adaptive Mutations ◽  
Furin Cleavage Site ◽  
Protein Receptor

Much can be learned from 1.2 million sequences of SARS-CoV-2 generated during the last 15 months. Out of the overwhelming number of mutations sampled so far, only few rose to prominence in the viral population. Many of these emerged recently and independently in multiple lineages. Such a textbook example of convergent evolution at the molecular level is not only curiosity but a guide to uncover the basis for adaptive advantage behind these events. Focusing on the extent of the convergent evolution in the spike (S) protein, our report confirms that the most concerning SARS-CoV-2 lineages carry the heaviest burden of convergent S-protein mutations, suggesting their fundamental adaptive advantage. The great majority (21/25) of S-protein sites under convergent evolution tightly cluster in three functional domains; N-terminal domain, receptor-binding domain, and Furin cleavage site. We further show that among the S-protein receptor-binding motif mutations, ACE2 affinity-improving substitutions are favored. While the probed mutation space in the S protein covered all amino-acids reachable by single nucleotide changes, substitutions requiring two nucleotide changes or epistatic mutations of multiple-residues have only recently started to emerge. Unfortunately, despite their convergent emergence and physical association, most of these adaptive mutations and their combinations remain understudied. We aim to promote research of current variants which are currently understudied but may become important in the future.

scholarly journals Comprehensive Structural and Molecular Comparison of Spike Proteins of SARS-CoV-2, SARS-CoV and MERS-CoV, and Their Interactions with ACE2

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2638 ◽  
Author(s):  
Ma’mon M. Hatmal ◽  
Walhan Alshaer ◽  
Mohammad A. I. Al-Hatamleh ◽  
Malik Hatmal ◽  
Othman Smadi ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Binding Motif ◽  
Intermediate Hosts ◽  
Protein Structure Analysis ◽  
S Protein ◽  
Binding Characteristics ◽  
Protein Receptor ◽  
Genes Encoding ◽  
Tertiary Protein Structure ◽  
Molecular Comparison

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has recently emerged in China and caused a disease called coronavirus disease 2019 (COVID-19). The virus quickly spread around the world, causing a sustained global outbreak. Although SARS-CoV-2, and other coronaviruses, SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV) are highly similar genetically and at the protein production level, there are significant differences between them. Research has shown that the structural spike (S) protein plays an important role in the evolution and transmission of SARS-CoV-2. So far, studies have shown that various genes encoding primarily for elements of S protein undergo frequent mutation. We have performed an in-depth review of the literature covering the structural and mutational aspects of S protein in the context of SARS-CoV-2, and compared them with those of SARS-CoV and MERS-CoV. Our analytical approach consisted in an initial genome and transcriptome analysis, followed by primary, secondary and tertiary protein structure analysis. Additionally, we investigated the potential effects of these differences on the S protein binding and interactions to angiotensin-converting enzyme 2 (ACE2), and we established, after extensive analysis of previous research articles, that SARS-CoV-2 and SARS-CoV use different ends/regions in S protein receptor-binding motif (RBM) and different types of interactions for their chief binding with ACE2. These differences may have significant implications on pathogenesis, entry and ability to infect intermediate hosts for these coronaviruses. This review comprehensively addresses in detail the variations in S protein, its receptor-binding characteristics and detailed structural interactions, the process of cleavage involved in priming, as well as other differences between coronaviruses.

scholarly journals ACE2 glycans preferentially interact with the RBD of SARS-CoV-2 over SARS-CoV

2021 ◽  
Author(s):  
Atanu Acharya ◽  
Diane Lynch ◽  
Anna Pavlova ◽  
Yui Tik Pang ◽  
James Gumbart
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Cell Receptor ◽  
Glycosylation Site ◽  
Distinct Difference ◽  
S Protein ◽  
Binding Domains ◽  
Host Cell Receptor ◽  
Protein Receptor

We report a distinct difference in the interactions of the glycans of the host-cell receptor, ACE2, with SARS-CoV-2 and SARS-CoV S-protein receptor-binding domains (RBDs). Our analysis demonstrates that the ACE2 glycan at N90 may offer protection against infections of both coronaviruses, while the ACE2 glycan at N322 enhances interactions with the SARS-CoV-2 RBD. The interactions of the ACE2 glycan at N322 with SARS-CoV RBD are blocked by the presence of the RBD glycan at N357 of the SARS-CoV RBD. The absence of this glycosylation site on SARS-CoV-2 RBD may enhance its binding with ACE2.

scholarly journals Roadmap to developing a recombinant coronavirus S protein receptor-binding domain vaccine for severe acute respiratory syndrome

2012 ◽  
Vol 11 (12) ◽  
pp. 1405-1413 ◽  
Author(s):  
Shibo Jiang ◽  
Maria Elena Bottazzi ◽  
Lanying Du ◽  
Sara Lustigman ◽  
Chien-Te Kent Tseng ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Receptor Binding ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Protein Receptor

scholarly journals Structural Insights into Immune Recognition of the Severe Acute Respiratory Syndrome Coronavirus S Protein Receptor Binding Domain

2009 ◽  
Vol 388 (4) ◽  
pp. 815-823 ◽  
Author(s):  
John E. Pak ◽  
Chetna Sharon ◽  
Malathy Satkunarajah ◽  
Thierry C. Auperin ◽  
Cheryl M. Cameron ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Receptor Binding ◽  
Binding Domain ◽  
Immune Recognition ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Protein Receptor ◽  
Structural Insights

scholarly journals Structural remodeling of SARS-CoV-2 spike protein glycans reveals the regulatory roles in receptor binding affinity

2021 ◽  
Author(s):  
Yen-Pang Hsu ◽  
Debopreeti Mukherjee ◽  
Vladimir Shchurik ◽  
Alexey Makarov ◽  
Benjamin F. Mann
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Receptor Binding Affinity ◽  
Protein Receptor ◽  
Regulatory Effects

AbstractGlycans of the SARS-CoV-2 spike protein are speculated to play functional roles in the infection processes as they extensively cover the protein surface and are highly conserved across the variants. To date, the spike protein has become the principal target for vaccine and therapeutic development while the exact effects of its glycosylation remain elusive. Experimental reports have described the heterogeneity of the spike protein glycosylation profile. Subsequent molecular simulation studies provided a knowledge basis of the glycan functions. However, there are no studies to date on the role of discrete glycoforms on the spike protein pathobiology. Building an understanding of its role in SARS-CoV-2 is important as we continue to develop effective medicines and vaccines to combat the disease. Herein, we used designed combinations of glycoengineering enzymes to simplify and control the glycosylation profile of the spike protein receptor-binding domain (RBD). Measurements of the receptor binding affinity revealed the regulatory effects of the RBD glycans. Remarkably, opposite effects were observed from differently remodeled glycans, which presents a potential strategy for modulating the spike protein behaviors through glycoengineering. Moreover, we found that the reported anti-SARS-CoV-(2) antibody, S309, neutralizes the impact of different RBD glycoforms on the receptor binding affinity. Overall, this work reports the regulatory roles that glycosylation plays in the interaction between the viral spike protein and host receptor, providing new insights into the nature of SARS-CoV-2. Beyond this study, enzymatic remodeling of glycosylation offers the opportunity to understand the fundamental role of specific glycoforms on glycoconjugates across molecular biology.Covert art LegendsThe glycosylation of the SARS-CoV-2 spike protein receptor-binding domain has regulatory effects on the receptor binding affinity. Sialylation or not determines the “stabilizing” or “destabilizing” effect of the glycans. (Protein structure model is adapted from Protein Data Bank: 6moj. The original model does not contain the glycan structure.)SignificanceGlycans extensively cover the surface of SARS-CoV-2 spike (S) protein but the relationships between the glycan structures and the protein pathological behaviors remain elusive. Herein, we simplified and harmonized the glycan structures in the S protein receptor-binding domain and reported their regulatory roles in human receptor interaction. Opposite regulatory effects were observed and were determined by discrete glycan structures, which can be neutralized by the reported S309 antibody binding to the S protein. This report provides new insight into the mechanism of SARS-CoV-2 S protein infection as well as S309 neutralization.

scholarly journals Possible host-adaptation of SARS-CoV-2 due to improved ACE2 receptor binding in mink

2020 ◽  
Author(s):  
Matthijs R A Welkers ◽  
Alvin X Han ◽  
Chantal B E M Reusken ◽  
Dirk Eggink
Keyword(s):  
Immune Responses ◽  
Receptor Binding ◽  
Host Adaptation ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Protein Receptor ◽  
The Mean ◽  
Potential Adaptation

Abstract SARS-CoV-2 infections on mink farms are increasingly observed in several countries, leading to the massive culling of animals on affected farms. Recent studies showed multiple (anthropo)zoonotic transmission events between humans and mink on these farms. Mink-derived SARS-CoV-2 sequences from The Netherlands and Denmark contain multiple substitutions in the S protein receptor binding domain (RBD). Molecular modeling showed that these substitutions increase the mean binding energy, suggestive of potential adaptation of the SARS-CoV-2 S protein to the mink ACE2 receptor. These substitutions could possibly also impact human ACE2 binding affinity as well as humoral immune responses directed to the RBD region of the SARS-CoV-2 S protein in humans. We wish to highlight these observations to raise awareness and urge for the continued surveillance of mink (and other animal)-related infections.

scholarly journals Antigenicity and immunogenicity of SARS-CoV S protein receptor-binding domain stably expressed in CHO cells

2009 ◽  
Vol 384 (4) ◽  
pp. 486-490 ◽  
Author(s):  
Lanying Du ◽  
Guangyu Zhao ◽  
Lin Li ◽  
Yuxian He ◽  
Yusen Zhou ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Cho Cells ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Protein Receptor

ACE2 glycans preferentially interact with SARS-CoV-2 over SARS-CoV

2021 ◽  
Author(s):  
Atanu Acharya ◽  
Diane L. Lynch ◽  
Anna Pavlova ◽  
Yui Tik Pang ◽  
James Gumbart
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Cell Receptor ◽  
Distinct Difference ◽  
S Protein ◽  
Binding Domains ◽  
Host Cell Receptor ◽  
Protein Receptor

We report a distinct difference in the interactions of the glycans of the host-cell receptor, ACE2, with SARS-CoV-2 and SARS-CoV S-protein receptor-binding domains (RBDs). Our analysis demonstrates that the ACE2...

scholarly journals SARS-CoV-2, Early Entry Events

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
James P. Chambers ◽  
Jieh Yu ◽  
James J. Valdes ◽  
Bernard P. Arulanandam
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Cell Types ◽  
Proteolytic Processing ◽  
Binding Motif ◽  
Susceptible Host ◽  
S Protein ◽  
Protein Receptor ◽  
Specific Protease

Viruses are obligate intracellular parasites, and host cell entry is the first step in the viral life cycle. The SARS-CoV-2 (COVID-19) entry process into susceptible host tissue cells is complex requiring (1) attachment of the virus via the conserved spike (S) protein receptor-binding motif (RBM) to the host cell angiotensin-converting-enzyme 2 (ACE2) receptor, (2) S protein proteolytic processing, and (3) membrane fusion. Spike protein processing occurs at two cleavage sites, i.e., S1/S2 and S 2 ′ . Cleavage at the S1/S2 and S 2 ′ sites ultimately gives rise to generation of competent fusion elements important in the merging of the host cell and viral membranes. Following cleavage, shedding of the S1 crown results in significant conformational changes and fusion peptide repositioning for target membrane insertion and fusion. Identification of specific protease involvement has been difficult due to the many cell types used and studied. However, it appears that S protein proteolytic cleavage is dependent on (1) furin and (2) serine protease transmembrane protease serine 2 proteases acting in tandem. Although at present not clear, increased SARS-CoV-2 S receptor-binding motif binding affinity and replication efficiency may in part account for observed differences in infectivity. Cleavage of the ACE2 receptor appears to be yet another layer of complexity in addition to forfeiture and/or alteration of ACE2 function which plays an important role in cardiovascular and immune function.

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