An Updated Review on SARS-CoV-2 Main Proteinase (MPro): Protein Structure and Small-Molecule Inhibitors

2020 ◽  
Vol 20 ◽  
Author(s):  
Dima A. Sabbah ◽  
Rima Hajjo ◽  
Sanaa K. Bardaweel ◽  
Haizhen A. Zhong
Keyword(s):  
Viral Pathogenesis ◽  
Host Cells ◽  
The Novel ◽  
Medical Field ◽  
Disease Pathogenesis ◽  
S Protein ◽  
Host Tropism ◽  
Significant Interest ◽  
Novel Coronavirus ◽  
Corona Viruses

: Coronaviruses (CoVs) are enveloped positive-stranded RNA viruses with spike (S) protein projections that allow the virus to enter and infect host cells. The S protein is a key virulence factor determining viral pathogenesis, host tropism, and disease pathogenesis. There are currently diverse corona viruses that are known to cause disease in humans. The occurrence of Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), as fatal human CoV diseases, has induced significant interest in the medical field. The novel coronavirus disease (COVID-19) is an infectious disease caused by a novel strain of coronavirus (SAR-CoV-2). The SARSCoV2 outbreak has been evolved in Wuhan, China, in December 2019, and identified as a pandemic on March 2020 resulting in 53.24 M cases and 1.20M deaths worldwide. SARS-CoV-2 main proteinase (MPro), a key protease of CoV-2, mediates viral replication and transcription. SARS-CoV-2 MPro has been emerged as an attractive target for SARS-CoV-2 drug design and development. Diverse scaffolds have been released targeting SARS-CoV-2 MPro. In this review, we culminate the latest published information about SARS-CoV-2 main proteinase (MPro) and reported inhibitors.

scholarly journals Distinct Structural Flexibility within SARS-CoV-2 Spike Protein Reveals Potential Therapeutic Targets

2020 ◽  
Author(s):  
Serena H. Chen ◽  
M. Todd Young ◽  
John Gounley ◽  
Christopher Stanley ◽  
Debsindhu Bhowmik
Keyword(s):  
Host Cells ◽  
Dynamics Simulation ◽  
Structural Flexibility ◽  
The Novel ◽  
Simulation Approach ◽  
S Protein ◽  
Therapeutic Development ◽  
Human Coronaviruses ◽  
Novel Coronavirus ◽  
S Proteins

AbstractThe emergence and rapid worldwide spread of the novel coronavirus disease, COVID-19, has prompted concerted efforts to find successful treatments. The causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), uses its spike (S) protein to gain entry into host cells. Therefore, the S protein presents a viable target to develop a directed therapy. Here, we deployed an integrated artificial intelligence with molecular dynamics simulation approach to provide new details of the S protein structure. Based on a comprehensive structural analysis of S proteins from SARS-CoV-2 and previous human coronaviruses, we found that the protomer state of S proteins is structurally flexible. Without the presence of a stabilizing beta sheet from another protomer chain, two regions in the S2 domain and the hinge connecting the S1 and S2 subunits lose their secondary structures. Interestingly, the region in the S2 domain was previously identified as an immunodominant site in the SARS-CoV-1 S protein. We anticipate that the molecular details elucidated here will assist in effective therapeutic development for COVID-19.

scholarly journals Investigation of the genetic variation in ACE2 on the structural recognition by the novel coronavirus (SARS-CoV-2)

2020 ◽  
Author(s):  
Xingyi Guo ◽  
Zhishan Chen ◽  
Yumin Xia ◽  
Weiqiang Lin ◽  
Hongzhi Li
Keyword(s):  
Genetic Variation ◽  
The Novel ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Missense Variants ◽  
Catalytic Metal ◽  
Using Data ◽  
Novel Coronavirus ◽  
Insight Into

Abstract Background: The outbreak of coronavirus disease (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), through its surface spike glycoprotein (S-protein) recognition on the receptor Angiotensin-converting enzyme 2 (ACE2) in humans. However, it remains unclear how genetic variations in ACE2 may affect its function and structure, and consequently alter the recognition by SARS-CoV-2. Methods: We have systemically characterized missense variants in the gene ACE2 using data from the Genome Aggregation Database (gnomAD; N = 141,456). To investigate the putative deleterious role of missense variants, six existing functional prediction tools were applied to evaluate their impact. We further analyzed the structural flexibility of ACE2 and its protein-protein interface with the S-protein of SARS-CoV-2 using our developed Legion Interfaces Analysis (LiAn) program.Results: Here, we characterized a total of 12 ACE2 putative deleterious missense variants. Of those 12 variants, we further showed that p.His378Arg could directly weaken the binding of catalytic metal atom to decrease ACE2 activity and p.Ser19Pro could distort the most important helix to the S-protein. Another seven missense variants may affect secondary structures (i.e. p.Gly211Arg; p.Asp206Gly; p.Arg219Cys; p.Arg219His, p.Lys341Arg, p.Ile468Val, and p.Ser547Cys), whereas p.Ile468Val with AF = 0.01 is only present in Asian.Conclusions: We provide strong evidence of putative deleterious missense variants in ACE2 that are present in specific populations, which could disrupt the function and structure of ACE2. These findings provide novel insight into the genetic variation in ACE2 which may affect the SARS-CoV-2 recognition and infection, and COVID-19 susceptibility and treatment.

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 Targeting the sAC-Dependent cAMP Pool to Prevent SARS-Cov-2 Infection

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1962
Author(s):  
Muhammad Aslam ◽  
Yury Ladilov
Keyword(s):  
Endocytic Pathway ◽  
Host Cells ◽  
The Novel ◽  
Cellular Mechanisms ◽  
Late Endosomes ◽  
Proven Efficacy ◽  
Potential Impact ◽  
Potential Strategy ◽  
Novel Coronavirus ◽  
High Level

An outbreak of the novel coronavirus (CoV) SARS-CoV-2, the causative agent of COVID-19 respiratory disease, infected millions of people since the end of 2019, led to high-level morbidity and mortality and caused worldwide social and economic disruption. There are currently no antiviral drugs available with proven efficacy or vaccines for its prevention. An understanding of the underlying cellular mechanisms involved in virus replication is essential for repurposing the existing drugs and/or the discovery of new ones. Endocytosis is the important mechanism of entry of CoVs into host cells. Endosomal maturation followed by the fusion with lysosomes are crucial events in endocytosis. Late endosomes and lysosomes are characterized by their acidic pH, which is generated by a proton transporter V-ATPase and required for virus entry via endocytic pathway. The cytoplasmic cAMP pool produced by soluble adenylyl cyclase (sAC) promotes V-ATPase recruitment to endosomes/lysosomes and thus their acidification. In this review, we discuss targeting the sAC-specific cAMP pool as a potential strategy to impair the endocytic entry of the SARS-CoV-2 into the host cell. Furthermore, we consider the potential impact of sAC inhibition on CoV-induced disease via modulation of autophagy and apoptosis.

scholarly journals Repurposing Therapeutics for COVID-19: Supercomputer-Based Docking to the SARS-CoV-2 Viral Spike Protein and Viral Spike Protein-Human ACE2 Interface

2020 ◽  
Author(s):  
Micholas Smith ◽  
Jeremy C. Smith
Keyword(s):  
Small Molecules ◽  
High Throughput Screening ◽  
Protein S ◽  
Host Cells ◽  
Spike Protein ◽  
The Novel ◽  
S Protein ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Ranked List

The novel Wuhan coronavirus (SARS-CoV-2) has been sequenced, and the virus shares substantial similarity with SARS-CoV. Here, using a computational model of the spike protein (S-protein) of SARS-CoV-2 interacting with the human ACE2 receptor, we make use of the world's most powerful supercomputer, SUMMIT, to enact an ensemble docking virtual high-throughput screening campaign and identify small-molecules which bind to either the isolated Viral S-protein at its host receptor region or to the S protein-human ACE2 interface. We hypothesize the identified small-molecules may be repurposed to limit viral recognition of host cells and/or disrupt host-virus interactions. A ranked list of compounds is given that can be tested experimentally.<br>

scholarly journals Repurposing Therapeutics for COVID-19: Supercomputer-Based Docking to the SARS-CoV-2 Viral Spike Protein and Viral Spike Protein-Human ACE2 Interface

2020 ◽  
Author(s):  
Micholas Smith ◽  
Jeremy C. Smith
Keyword(s):  
Small Molecules ◽  
High Throughput Screening ◽  
Protein S ◽  
Host Cells ◽  
Spike Protein ◽  
The Novel ◽  
S Protein ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Ranked List

The novel Wuhan coronavirus (SARS-CoV-2) has been sequenced, and the virus shares substantial similarity with SARS-CoV. Here, using a computational model of the spike protein (S-protein) of SARS-CoV-2 interacting with the human ACE2 receptor, we make use of the world's most powerful supercomputer, SUMMIT, to enact an ensemble docking virtual high-throughput screening campaign and identify small-molecules which bind to either the isolated Viral S-protein at its host receptor region or to the S protein-human ACE2 interface. We hypothesize the identified small-molecules may be repurposed to limit viral recognition of host cells and/or disrupt host-virus interactions. A ranked list of compounds is given that can be tested experimentally.<br>

scholarly journals Conservation analysis and screening of Ayurvedic compounds against SARS-CoV-2 Spike protein

2020 ◽  
Author(s):  
Zarrin Basharat ◽  
Muhammad Jahanzaib ◽  
Noor Rahman ◽  
Ishtiaq Ahmad Khan ◽  
Azra Yasmin
Keyword(s):  
Caspase 3 ◽  
Spike Protein ◽  
The Novel ◽  
Post Translational Modification ◽  
S Protein ◽  
Conservation Analysis ◽  
The Past ◽  
Online Tools ◽  
Novel Coronavirus ◽  
Over Time

Abstract Recent infections caused by the novel coronavirus (SARS-CoV-2) have led to global panic and mortality. Here, we analyzed the spike (S) protein of this virus using bioinformatics tools. We aimed to determine relative changes among different coronavirus species over the past two decades and to understand the conservation of the S-protein. Representative sequences of coronaviruses were collected from humans and other animals between 2000 and 2020. Evolutionary analyses found that the S-protein did not evolve overnight, but rather continuously over time. Post-translational modification (PTM) analysis using online tools and virtual screening of S-protein against a phytochemical database of Ayurvedic medicinal compounds (n = 2103) identified the S-protein inhibitors. Among these, top ranked were Gingerol (IUPAC name: 4'-Me ether, 3,5-di-Ac 3,5-di-Gingerdiols), 1-(5-Butyltetrahydro-2-furanyl)-2-hexacosanone and Ginsenoyne N ginseng that stimulates Caspase-3, Caspase-8, and the immune system. Gingerol is found in the fresh ginger and has reputation of being a potent antiviral. These compounds might prove useful to design drugs against COVID-19.

scholarly journals COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism

2020 ◽  
Author(s):  
liu wenzhong ◽  
Li hualan
Keyword(s):  
Carbon Dioxide ◽  
Rna Virus ◽  
Host Cells ◽  
Surface Glycoprotein ◽  
The Novel ◽  
Beta Chain ◽  
Positive Strand Rna Virus ◽  
Novel Coronavirus ◽  
Positive Strand Rna ◽  
Bat Coronavirus

<p>The novel coronavirus pneumonia (COVID-19) is an infectious acute respiratory infection caused by the novel coronavirus. The virus is a positive-strand RNA virus with high homology to bat coronavirus. In this study, conserved domain analysis, homology modeling, and molecular docking were used to compare the biological roles of certain proteins of the novel coronavirus. The results showed the ORF8 and surface glycoprotein could bind to the porphyrin, respectively. At the same time, orf1ab, ORF10, and ORF3a proteins could coordinate attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the porphyrin. The attack will cause less and less hemoglobin that can carry oxygen and carbon dioxide. The lung cells have extremely intense poisoning and inflammatory due to the inability to exchange carbon dioxide and oxygen frequently, which eventually results in ground-glass-like lung images. The mechanism also interfered with the normal heme anabolic pathway of the human body, is expected to result in human disease. According to the validation analysis of these finds, chloroquine could prevent orf1ab, ORF3a, and ORF10 to attack the heme to form the porphyrin, and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent, effectively relieve the symptoms of respiratory distress. Favipiravir could inhibit the envelope protein and ORF7a protein bind to porphyrin, prevent the virus from entering host cells, and catching free porphyrins. Because the novel coronavirus is dependent on porphyrins, it may originate from an ancient virus. Therefore, this research is of high value to contemporary biological experiments, disease prevention, and clinical treatment.<br></p>

scholarly journals ACE-2-derived Biomimetic Peptides for the Inhibition of Spike Protein of SARS-CoV-2

2020 ◽  
Author(s):  
Saroj Kumar Panda ◽  
Parth Sarthi Sen Gupta ◽  
Satyaranjan Biswal ◽  
Abhik Kumar Ray ◽  
Malay Kumar Rana
Keyword(s):  
Principal Component ◽  
Host Cells ◽  
Spike Protein ◽  
Peptide Inhibitor ◽  
The Novel ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Inhibition Assay ◽  
Angiotensin Converting Enzyme 2 ◽  
Novel Coronavirus

<p>SARS-CoV-2, a novel coronavirus causing overwhelming death and infection worldwide, has emerged as a pandemic. Compared to its predecessor SARS-CoV, SARS-CoV-2 is more infective for being highly contagious and exhibiting tighter binding with host angiotensin-converting enzyme 2 (hACE-2). The entry of the virus into host cells is mediated by the interaction of its spike protein with hACE-2. Thus, a peptide that has a resemblance to hACE-2 but can overpower the spike protein-hACE-2 interaction will be a potential therapeutic to contain this virus. The non-interacting residues in the receptor-binding domain of hACE-2 have been mutated to generate a library of 136 new peptides. Out of this library, docking and virtual screening discover seven peptides that can exert a stronger interaction with the spike protein than hACE-2. A peptide derived from simultaneous mutation of all the non-interacting residues of hACE-2 yields two-fold stronger interaction than hACE-2 and thus turns out here to be the best peptide-inhibitor of the novel coronavirus. The binding of the spike protein and the best peptide-inhibitor with hACE-2 is explored further by molecular dynamics, free energy, and principal component analysis to demonstrate its efficacy. Further, the inhibition assay study with the best peptide inhibitor is in progress. </p>

scholarly journals COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism

2020 ◽  
Author(s):  
liu wenzhong ◽  
Li hualan
Keyword(s):  
Carbon Dioxide ◽  
Rna Virus ◽  
Host Cells ◽  
Surface Glycoprotein ◽  
The Novel ◽  
Beta Chain ◽  
Positive Strand Rna Virus ◽  
Novel Coronavirus ◽  
Positive Strand Rna ◽  
Bat Coronavirus

<p>The novel coronavirus pneumonia (COVID-19) is an infectious acute respiratory infection caused by the novel coronavirus. The virus is a positive-strand RNA virus with high homology to bat coronavirus. In this study, conserved domain analysis, homology modeling, and molecular docking were used to compare the biological roles of certain proteins of the novel coronavirus. The results showed the ORF8 and surface glycoprotein could bind to the porphyrin, respectively. At the same time, orf1ab, ORF10, and ORF3a proteins could coordinate attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the porphyrin. The attack will cause less and less hemoglobin that can carry oxygen and carbon dioxide. The lung cells have extremely intense poisoning and inflammatory due to the inability to exchange carbon dioxide and oxygen frequently, which eventually results in ground-glass-like lung images. The mechanism also interfered with the normal heme anabolic pathway of the human body, is expected to result in human disease. According to the validation analysis of these finds, chloroquine could prevent orf1ab, ORF3a, and ORF10 to attack the heme to form the porphyrin, and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent, effectively relieve the symptoms of respiratory distress. Favipiravir could inhibit the envelope protein and ORF7a protein bind to porphyrin, prevent the virus from entering host cells, and catching free porphyrins. Because the novel coronavirus is dependent on porphyrins, it may originate from an ancient virus. Therefore, this research is of high value to contemporary biological experiments, disease prevention, and clinical treatment.<br></p>

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