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1.
Acta Crystallogr D Struct Biol ; 77(Pt 8): 1040-1049, 2021 Aug 01.
Article in English | MEDLINE | ID: covidwho-1341166

ABSTRACT

The ß-link is a composite protein motif consisting of a G1ß ß-bulge and a type II ß-turn, and is generally found at the end of two adjacent strands of antiparallel ß-sheet. The 1,2-positions of the ß-bulge are also the 3,4-positions of the ß-turn, with the result that the N-terminal portion of the polypeptide chain is orientated at right angles to the ß-sheet. Here, it is reported that the ß-link is frequently found in certain protein folds of the SCOPe structural classification at specific locations where it connects a ß-sheet to another area of a protein. It is found at locations where it connects one ß-sheet to another in the ß-sandwich and related structures, and in small (four-, five- or six-stranded) ß-barrels, where it connects two ß-strands through the polypeptide chain that crosses an open end of the barrel. It is not found in larger (eight-stranded or more) ß-barrels that are straightforward ß-meanders. In some cases it initiates a connection between a single ß-sheet and an α-helix. The ß-link also provides a framework for catalysis in serine proteases, where the catalytic serine is part of a conserved ß-link, and in cysteine proteases, including Mpro of human SARS-CoV-2, in which two residues of the active site are located in a conserved ß-link.


Subject(s)
Protein Structure, Secondary , Serine Proteases/chemistry , Amino Acid Motifs , Animals , Catalytic Domain , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Cysteine Proteases/chemistry , Cysteine Proteases/metabolism , Databases, Protein , Humans , Hydrogen Bonding , Models, Molecular , SARS-CoV-2/chemistry , SARS-CoV-2/enzymology , Serine Proteases/metabolism , Structural Homology, Protein
2.
Bioengineered ; 12(1): 2836-2850, 2021 12.
Article in English | MEDLINE | ID: covidwho-1297360

ABSTRACT

Angiotensin I-converting enzyme 2 (ACE2), type II transmembrane serine protease 2 and 4 (TMPRSS2 and TMPRSS4) are important receptors for SARS-CoV-2 infection. In this study, the full-length tree shrewACE2 gene was cloned and sequenced, and its biological information was analyzed. The expression levels of ACE2, TMPRSS2 and TMPRSS4 in various tissues or organs of the tree shrew were detected. The results showed that the full-length ACE2 gene in tree shrews was 2,786 bp, and its CDS was 2,418 bp, encoding 805 amino acids. Phylogenetic analysis based on the CDS of ACE2 revealed that tree shrews were more similar to rabbits (85.93%) and humans (85.47%) but far from mice (82.81%) and rats (82.58%). In silico analysis according to the binding site of SARS-CoV-2 with the ACE2 receptor of different species predicted that tree shrews had potential SARS-CoV-2 infection possibility, which was similar to that of rabbits, cats and dogs but significantly higher than that of mice and rats. In addition, various tissues or organs of tree shrews expressed ACE2, TMPRSS2 and TMPRSS4. Among them, the kidney most highly expressed ACE2, followed by the lung and liver. The esophagus, lung, liver, intestine and kidney had relatively high expression levels of TMPRSS2 and TMPRSS4. In general, we reported for the first time the expression of ACE2, TMPRSS2 and TMPRSS4 in various tissues or organs in tree shrews. Our results revealed that tree shrews could be used as a potential animal model to study the mechanism underlying SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/etiology , Membrane Proteins/genetics , SARS-CoV-2 , Serine Endopeptidases/genetics , Tupaiidae/genetics , Tupaiidae/metabolism , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Bioengineering , COVID-19/enzymology , COVID-19/genetics , Computational Biology , Disease Models, Animal , Female , Humans , Male , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Models, Molecular , Phylogeny , Protein Structure, Tertiary , Sequence Homology, Amino Acid , Serine Endopeptidases/chemistry , Serine Endopeptidases/metabolism , Structural Homology, Protein , Tissue Distribution , Tupaiidae/virology
3.
Nat Commun ; 12(1): 3433, 2021 06 08.
Article in English | MEDLINE | ID: covidwho-1261998

ABSTRACT

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has created global health and economic emergencies. SARS-CoV-2 viruses promote their own spread and virulence by hijacking human proteins, which occurs through viral protein recognition of human targets. To understand the structural basis for SARS-CoV-2 viral-host protein recognition, here we use cryo-electron microscopy (cryo-EM) to determine a complex structure of the human cell junction protein PALS1 and SARS-CoV-2 viral envelope (E) protein. Our reported structure shows that the E protein C-terminal DLLV motif recognizes a pocket formed exclusively by hydrophobic residues from the PDZ and SH3 domains of PALS1. Our structural analysis provides an explanation for the observation that the viral E protein recruits PALS1 from lung epithelial cell junctions. In addition, our structure provides novel targets for peptide- and small-molecule inhibitors that could block the PALS1-E interactions to reduce E-mediated virulence.


Subject(s)
Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/metabolism , Intercellular Junctions/metabolism , Membrane Proteins/metabolism , Nucleoside-Phosphate Kinase/metabolism , Amino Acid Sequence , Coronavirus Envelope Proteins/ultrastructure , Cryoelectron Microscopy , Humans , Protein Domains , SARS-CoV-2/physiology , Structural Homology, Protein , Structure-Activity Relationship
4.
Proteins ; 89(2): 163-173, 2021 02.
Article in English | MEDLINE | ID: covidwho-745464

ABSTRACT

Human interleukin-6 (hIL-6) is a multifunctional cytokine that regulates immune and inflammatory responses in addition to metabolic and regenerative processes and cancer. hIL-6 binding to the IL-6 receptor (IL-6Rα) induces homodimerization and recruitment of the glycoprotein (gp130) to form a hexameric signaling complex. Anti-IL-6 and IL-6R antibodies are clinically approved inhibitors of IL-6 signaling pathway for treating rheumatoid arthritis and Castleman's disease, respectively. There is a potential to develop novel small molecule IL-6 antagonists derived from understanding the structural basis for IL-6/IL-6Rα interactions. Here, we combine homology modeling with extensive molecular dynamics (MD) simulations to examine the association of hIL-6 with IL-6Rα. A comparison with MD of apo hIL-6 reveals that the binding of hIL-6 to IL-6Rα induces structural and dynamic rearrangements in the AB loop region of hIL-6, disrupting intraprotein contacts and increasing the flexibility of residues 48 to 58 of the AB loop. In contrast, due to the involvement of residues 59 to 78 in forming contacts with the receptor, these residues of the AB loop are observed to rigidify in the presence of the receptor. The binary complex is primarily stabilized by two pairs of salt bridges, Arg181 (hIL-6)- Glu182 (IL-6Rα) and Arg184 (hIL-6)- Glu183 (IL-6Rα) as well as hydrophobic and aromatic stacking interactions mediated essentially by Phe residues in both proteins. An interplay of electrostatic, hydrophobic, hydrogen bonding, and aromatic stacking interactions facilitates the formation of the hIL-6/IL-6Rα complex.


Subject(s)
Apoproteins/chemistry , Interleukin-6/chemistry , Molecular Dynamics Simulation , Receptors, Interleukin-6/chemistry , Apoproteins/metabolism , Binding Sites , Crystallography, X-Ray , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Interleukin-6/metabolism , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Receptors, Interleukin-6/metabolism , Static Electricity , Structural Homology, Protein , Thermodynamics
5.
J Virol ; 94(22)2020 10 27.
Article in English | MEDLINE | ID: covidwho-982189

ABSTRACT

Coronaviruses (CoV) have caused a number of major epidemics in humans and animals, including the current pandemic of coronavirus disease 2019 (COVID-19), which has brought a renewed focus on the evolution and interspecies transmission of coronaviruses. Swine acute diarrhea syndrome coronavirus (SADS-CoV), which was recently identified in piglets in southern China, is an alphacoronavirus that originates from the same genus of horseshoe bats as severe acute respiratory syndrome CoV (SARS-CoV) and that was reported to be capable of infecting cells from a broad range of species, suggesting a considerable potential for interspecies transmission. Given the importance of the coronavirus spike (S) glycoprotein in host range determination and viral entry, we report a cryo-electron microscopy (cryo-EM) structure of the SADS-CoV S trimer in the prefusion conformation at a 3.55-Å resolution. Our structure reveals that the SADS-CoV S trimer assumes an intrasubunit quaternary packing mode in which the S1 subunit N-terminal domain (S1-NTD) and the S1 subunit C-terminal domain (S1-CTD) of the same protomer pack together by facing each other in the lying-down state. SADS-CoV S has several distinctive structural features that may facilitate immune escape, such as a relatively compact architecture of the S trimer and epitope masking by glycan shielding. Comparison of SADS-CoV S with the spike proteins of the other coronavirus genera suggested that the structural features of SADS-CoV S are evolutionarily related to those of the spike proteins of the other genera rather than to the spike protein of a typical alphacoronavirus. These data provide new insights into the evolutionary relationship between spike glycoproteins of SADS-CoV and those of other coronaviruses and extend our understanding of their structural and functional diversity.IMPORTANCE In this article, we report the atomic-resolution prefusion structure of the spike protein from swine acute diarrhea syndrome coronavirus (SADS-CoV). SADS-CoV is a pathogenic alphacoronavirus that was responsible for a large-scale outbreak of fatal disease in pigs and that was reported to be capable of interspecies transmission. We describe the overall structure of the SADS-CoV spike protein and conducted a detailed analysis of its main structural elements. Our results and analyses are consistent with those of previous phylogenetic studies and suggest that the SADS-CoV spike protein is evolutionarily related to the spike proteins of betacoronaviruses, with a strong similarity in S1-NTDs and a marked divergence in S1-CTDs. Moreover, we discuss the possible immune evasion strategies used by the SADS-CoV spike protein. Our study provides insights into the structure and immune evasion strategies of the SADS-CoV spike protein and broadens the understanding of the evolutionary relationships between coronavirus spike proteins of different genera.


Subject(s)
Alphacoronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/ultrastructure , Alphacoronavirus/genetics , Amino Acid Sequence , Cryoelectron Microscopy , Evolution, Molecular , Immune Evasion , Models, Molecular , Sequence Alignment , Spike Glycoprotein, Coronavirus/chemistry , Structural Homology, Protein
6.
PLoS One ; 15(8): e0237300, 2020.
Article in English | MEDLINE | ID: covidwho-842269

ABSTRACT

The outbreak of COVID-19 across the world has posed unprecedented and global challenges on multiple fronts. Most of the vaccine and drug development has focused on the spike proteins and viral RNA-polymerases and main protease for viral replication. Using the bioinformatics and structural modelling approach, we modelled the structure of the envelope (E)-protein of novel SARS-CoV-2. The E-protein of this virus shares sequence similarity with that of SARS- CoV-1, and is highly conserved in the N-terminus regions. Incidentally, compared to spike proteins, E proteins demonstrate lower disparity and mutability among the isolated sequences. Using homology modelling, we found that the most favorable structure could function as a gated ion channel conducting H+ ions. Combining pocket estimation and docking with water, we determined that GLU 8 and ASN 15 in the N-terminal region were in close proximity to form H-bonds which was further validated by insertion of the E protein in an ERGIC-mimic membrane. Additionally, two distinct "core" structures were visible, the hydrophobic core and the central core, which may regulate the opening/closing of the channel. We propose this as a mechanism of viral ion channeling activity which plays a critical role in viral infection and pathogenesis. In addition, it provides a structural basis and additional avenues for vaccine development and generating therapeutic interventions against the virus.


Subject(s)
Betacoronavirus/chemistry , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Envelope Proteins/chemistry , Viral Envelope Proteins/genetics , Betacoronavirus/isolation & purification , COVID-19 , COVID-19 Vaccines , Computer Simulation , Coronavirus Envelope Proteins , Coronavirus Infections/virology , Humans , Hydrogen , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Models, Molecular , Pneumonia, Viral/virology , Point Mutation , Protein Conformation , SARS-CoV-2 , Structural Homology, Protein , Vaccines, Attenuated , Vaccines, Inactivated , Viral Envelope Proteins/immunology , Viral Vaccines , Water/chemistry
7.
PLoS One ; 15(10): e0240004, 2020.
Article in English | MEDLINE | ID: covidwho-810225

ABSTRACT

The SARS-CoV-2 virus has caused a pandemic and is public health emergency of international concern. As of now, no registered therapies are available for treatment of coronavirus infection. The viral infection depends on the attachment of spike (S) glycoprotein to human cell receptor angiotensin-converting enzyme 2 (ACE2). We have designed a protein inhibitor (ΔABP-D25Y) targeting S protein using computational approach. The inhibitor consists of two α helical peptides homologues to protease domain (PD) of ACE2. Docking studies and molecular dynamic simulation revealed that the inhibitor binds exclusively at the ACE2 binding site of S protein. The computed binding affinity of the inhibitor is higher than the ACE2 and thus will likely out compete ACE2 for binding to S protein. Hence, the proposed inhibitor ΔABP-D25Y could be a potential blocker of S protein and receptor binding domain (RBD) attachment.


Subject(s)
Antiviral Agents/chemistry , Betacoronavirus/drug effects , Drug Design , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Structural Homology, Protein , Angiotensin-Converting Enzyme 2 , Binding Sites , COVID-19 , Computer Simulation , Coronavirus Infections , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral , Protein Domains , SARS-CoV-2
8.
J Mol Graph Model ; 100: 107710, 2020 11.
Article in English | MEDLINE | ID: covidwho-705608

ABSTRACT

The emergence of SARS-CoV-2 has prompted a worldwide health emergency. There is an urgent need for therapeutics, both through the repurposing of approved drugs and the development of new treatments. In addition to the viral drug targets, a number of human drug targets have been suggested. In theory, targeting human proteins should provide an advantage over targeting viral proteins in terms of drug resistance, which is commonly a problem in treating RNA viruses. This paper focuses on the human protein TMPRSS2, which supports coronavirus life cycles by cleaving viral spike proteins. The three-dimensional structure of TMPRSS2 is not known and so we have generated models of the TMPRSS2 in the apo state as well as in complex with a peptide substrate and putative inhibitors to aid future work. Importantly, many related human proteases have 80% or higher identity with TMPRSS2 in the S1-S1' subsites, with plasminogen and urokinase-type plasminogen activator (uPA) having 95% identity. We highlight 376 approved, investigational or experimental drugs targeting S1A serine proteases that may also inhibit TMPRSS2. Whilst the presence of a relatively uncommon lysine residue in the S2/S3 subsites means that some serine protease inhibitors will not inhibit TMPRSS2, this residue is likely to provide a handle for selective targeting in a focused drug discovery project. We discuss how experimental drugs targeting related serine proteases might be repurposed as TMPRSS2 inhibitors to treat coronaviruses.


Subject(s)
Antiviral Agents/chemistry , Betacoronavirus/chemistry , Protease Inhibitors/chemistry , Serine Endopeptidases/chemistry , Small Molecule Libraries/chemistry , Amino Acid Sequence , Betacoronavirus/enzymology , COVID-19 , Catalytic Domain , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drug Repositioning , Host-Pathogen Interactions , Humans , Ligands , Molecular Dynamics Simulation , Pandemics , Plasminogen/antagonists & inhibitors , Plasminogen/chemistry , Plasminogen/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , SARS-CoV-2 , Sequence Alignment , Serine Endopeptidases/metabolism , Structural Homology, Protein , Structure-Activity Relationship , Thermodynamics , Urokinase-Type Plasminogen Activator/antagonists & inhibitors , Urokinase-Type Plasminogen Activator/chemistry , Urokinase-Type Plasminogen Activator/metabolism
9.
J Med Virol ; 92(6): 584-588, 2020 06.
Article in English | MEDLINE | ID: covidwho-685102

ABSTRACT

Last December 2019, a new virus, named novel Coronavirus (COVID-2019) causing many cases of severe pneumonia was reported in Wuhan, China. The virus knowledge is limited and especially about COVID-2019 pathogenesis. The Open Reading Frame 1ab (ORF1ab) of COVID-2019 has been analyzed to evidence the presence of mutation caused by selective pressure on the virus. For selective pressure analysis fast-unconstrained Bayesian approximation (FUBAR) was used. Homology modelling has been performed by SwissModel and HHPred servers. The presence of transmembrane helical segments in Coronavirus ORF1ab non structural protein 2 (nsp2) and nsp3 was tested by TMHMM, MEMSAT, and MEMPACK tools. Three-dimensional structures have been analyzed and displayed using PyMOL. FUBAR analysis revealed the presence of potential sites under positive selective pressure (P < .05). Position 723 in the COVID-2019 has a serine instead a glycine residue, while at aminoacidic position 1010 a proline instead an isoleucine. Significant (P < .05) pervasive negative selection in 2416 sites (55%) was found. The positive selective pressure could account for some clinical features of this virus compared with severe acute respiratory syndrome (SARS) and Bat SARS-like CoV. The stabilizing mutation falling in the endosome-associated-protein-like domain of the nsp2 protein could account for COVID-2019 high ability of contagious, while the destabilizing mutation in nsp3 proteins could suggest a potential mechanism differentiating COVID-2019 from SARS. These data could be helpful for further investigation aimed to identify potential therapeutic targets or vaccine strategy, especially in the actual moment when the epidemic is ongoing and the scientific community is trying to enrich knowledge about this new viral pathogen.


Subject(s)
Betacoronavirus/genetics , SARS Virus/genetics , Viral Nonstructural Proteins/chemistry , Viral Proteins/chemistry , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/virology , Female , Gene Expression , Humans , Male , Models, Molecular , Mutation , Pandemics , Pneumonia, Viral/virology , Polyproteins , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS Virus/pathogenicity , SARS-CoV-2 , Selection, Genetic , Structural Homology, Protein , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Viral Proteins/genetics , Viral Proteins/metabolism
10.
Med Chem ; 17(4): 380-395, 2021.
Article in English | MEDLINE | ID: covidwho-688767

ABSTRACT

BACKGROUND: Globally, over 4.3 million laboratory confirmed cases of COVID-19 have been reported from over 105 countries. No FDA approved antiviral is available for the treatment of this infection. Zhavoronkov et al., with their generative chemistry pipeline, have generated structures that can be potential novel drug-like inhibitors for COVID-19, provided they are validated. 3C-like protease (3CLP) is a homodimeric cysteine protease that is present in coronaviruses. Interestingly, 3CLP is 96.1% structurally similar between SARS-CoV and SARS-CoV-2. OBJECTIVE: To evaluate interaction of generated structures with 3CLP of SARS-CoV (RCSB PDB ID: 4MDS). METHODS: Crystal structure of human SARS-CoV with a non-covalent inhibitor with resolution: 1.598 Å was obtained and molecular docking was performed to evaluate the interaction with generated structures. The MM-GBSA and IFD-SP were performed to narrow down to the structures with better binding energy and IFD score. The ADME analysis was performed on top 5 hits and further MD simulation was employed for top 2 hits. RESULTS: In XP docking, IFD-SP and molecular dynamic simulation studies, the top 2 hits 32 and 61 showed interaction with key amino acid residue GLU166. Structure 61, also showed interaction with HIS164. These interactions of generated structure 32 and 61, with GLU166 and HIS164, indicate the binding of the selected drug within the close proximity of 3CLP. In the MD simulation, the protein- ligand complex of 4MDS and structure 61 was found to be more stable for 10ns. CONCLUSION: These identified structures can be further assessed for their antiviral activity to combat SARS-CoV and COVID-19.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , SARS-CoV-2/chemistry , Small Molecule Libraries/chemistry , Antiviral Agents/metabolism , COVID-19/drug therapy , Catalytic Domain , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Drug Discovery , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/metabolism , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , SARS Virus/chemistry , SARS Virus/enzymology , SARS-CoV-2/enzymology , Small Molecule Libraries/metabolism , Structural Homology, Protein , Structure-Activity Relationship , Substrate Specificity , Thermodynamics , User-Computer Interface
11.
Nat Struct Mol Biol ; 27(8): 763-767, 2020 08.
Article in English | MEDLINE | ID: covidwho-640223

ABSTRACT

SARS-CoV-2 is thought to have emerged from bats, possibly via a secondary host. Here, we investigate the relationship of spike (S) glycoprotein from SARS-CoV-2 with the S protein of a closely related bat virus, RaTG13. We determined cryo-EM structures for RaTG13 S and for both furin-cleaved and uncleaved SARS-CoV-2 S; we compared these with recently reported structures for uncleaved SARS-CoV-2 S. We also biochemically characterized their relative stabilities and affinities for the SARS-CoV-2 receptor ACE2. Although the overall structures of human and bat virus S proteins are similar, there are key differences in their properties, including a more stable precleavage form of human S and about 1,000-fold tighter binding of SARS-CoV-2 to human receptor. These observations suggest that cleavage at the furin-cleavage site decreases the overall stability of SARS-CoV-2 S and facilitates the adoption of the open conformation that is required for S to bind to the ACE2 receptor.


Subject(s)
Betacoronavirus/genetics , Host-Pathogen Interactions/genetics , Peptidyl-Dipeptidase A/chemistry , Receptors, Virus/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/metabolism , Betacoronavirus/ultrastructure , Binding Sites , COVID-19 , Chiroptera/virology , Coronavirus Infections/virology , Cryoelectron Microscopy , Evolution, Molecular , Furin/chemistry , Gene Expression , HEK293 Cells , Humans , Models, Molecular , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Protein Isoforms/chemistry , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Stability , Proteolysis , Receptors, Virus/genetics , Receptors, Virus/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Structural Homology, Protein
12.
Biophys Chem ; 264: 106420, 2020 09.
Article in English | MEDLINE | ID: covidwho-623862

ABSTRACT

One notable feature of the SARS-CoV-2 genome, the spike (S) protein of SARS-CoV-2 has a polybasic furin cleavage site (FCS) at its S1-S2 boundary through the insertion of 12 nucleotides encoding four amino acid residues PRRA. Quite intriguingly, this polybasic FCS is absent in coronaviruses of the same clade as SARS-CoV-2. Thus, with currently available experimental structural data for S protein, this short article presents a set of comprehensive structural characterization of the insertion of FCS into S protein, and argues against a hypothesis of the origin of SARS-CoV-2 from purposeful manipulation: (1), the inserted FCS is spatially located at a random coil loop region, mostly distantly solvent-exposed (instead of deeply buried), with no structural proximity to the other part of the S protein; (2), the insertion of FCS itself does not alter, neither stabilize nor de-stabilize, the three-dimensional structure of S; (3), the net result here is the insertion of a furin cleavage site into S protein, whose S1 and S2 subunits will still be strongly electrostatically bonded together from a structural and biophysical point of view, even if the polybasic FCS is actually cleaved by furin protease before or after viral cell entry.


Subject(s)
Betacoronavirus/chemistry , Furin/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Amino Acid Sequence , Betacoronavirus/genetics , Gene Expression , Humans , Hydrogen Bonding , Models, Molecular , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Proteolysis , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Structural Homology, Protein
13.
J Allergy Clin Immunol ; 146(2): 330-331, 2020 08.
Article in English | MEDLINE | ID: covidwho-597639
14.
Virus Res ; 286: 198058, 2020 09.
Article in English | MEDLINE | ID: covidwho-591331

ABSTRACT

The 2019 novel coronavirus disease (COVID-19) that emerged in China has been declared as public health emergency of international concern by the World Health Organization and the causative pathogen was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this report, we analyzed the structural characteristics of the N-terminal domain of the S1 subunit (S1-NTD) of the SARS-CoV-2 spike protein in comparison to the SARS-CoV in particular, and to other viruses presenting similar characteristic in general. Given the severity and the wide and rapid spread of the SARS-CoV-2 infection, it is very likely that the virus recognizes other receptors/co-receptors besides the ACE2. The NTD of the SARS-CoV-2 contains a receptor-binding motif different from that of SARS-CoV, with some insertions that could confer to the new coronavirus new receptor binding abilities. In particular, motifs similar to the insertion 72GTNGTKR78 have been found in structural proteins of other viruses; and these motifs were located in putative regions involved in recognizing protein and sugar receptors, suggesting therefore that similar binding abilities could be displayed by the SARS-CoV-2 S1-NTD. Moreover, concerning the origin of these NTD insertions, our findings point towards an evolutionary acquisition rather than the hypothesis of an engineered virus.


Subject(s)
Betacoronavirus/chemistry , Middle East Respiratory Syndrome Coronavirus/chemistry , Peptidyl-Dipeptidase A/chemistry , Receptors, Virus/chemistry , SARS Virus/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Amino Acid Sequence , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/genetics , Betacoronavirus/metabolism , Binding Sites , COVID-19 , Chiroptera , Coronavirus Infections/pathology , Coronavirus Infections/virology , Evolution, Molecular , Gene Expression , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/metabolism , Models, Molecular , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS Virus/genetics , SARS Virus/metabolism , SARS-CoV-2 , Sequence Alignment , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Structural Homology, Protein , Thermodynamics , Virus Attachment
15.
Interdiscip Sci ; 12(3): 368-376, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-459220

ABSTRACT

A novel coronavirus, called 2019-nCoV, was recently found in Wuhan, Hubei Province of China, and now is spreading across China and other parts of the world. Although there are some drugs to treat 2019-nCoV, there is no proper scientific evidence about its activity on the virus. It is of high significance to develop a drug that can combat the virus effectively to save valuable human lives. It usually takes a much longer time to develop a drug using traditional methods. For 2019-nCoV, it is now better to rely on some alternative methods such as deep learning to develop drugs that can combat such a disease effectively since 2019-nCoV is highly homologous to SARS-CoV. In the present work, we first collected virus RNA sequences of 18 patients reported to have 2019-nCoV from the public domain database, translated the RNA into protein sequences, and performed multiple sequence alignment. After a careful literature survey and sequence analysis, 3C-like protease is considered to be a major therapeutic target and we built a protein 3D model of 3C-like protease using homology modeling. Relying on the structural model, we used a pipeline to perform large scale virtual screening by using a deep learning based method to accurately rank/identify protein-ligand interacting pairs developed recently in our group. Our model identified potential drugs for 2019-nCoV 3C-like protease by performing drug screening against four chemical compound databases (Chimdiv, Targetmol-Approved_Drug_Library, Targetmol-Natural_Compound_Library, and Targetmol-Bioactive_Compound_Library) and a database of tripeptides. Through this paper, we provided the list of possible chemical ligands (Meglumine, Vidarabine, Adenosine, D-Sorbitol, D-Mannitol, Sodium_gluconate, Ganciclovir and Chlorobutanol) and peptide drugs (combination of isoleucine, lysine and proline) from the databases to guide the experimental scientists and validate the molecules which can combat the virus in a shorter time.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Deep Learning , Drug Evaluation, Preclinical/methods , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Viral Nonstructural Proteins/antagonists & inhibitors , Amino Acid Sequence , Antiviral Agents/chemistry , Betacoronavirus/genetics , COVID-19 , Catalytic Domain , Coronavirus 3C Proteases , Coronavirus Infections/epidemiology , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/genetics , Databases, Nucleic Acid , Databases, Pharmaceutical , Drug Design , Drug Evaluation, Preclinical/statistics & numerical data , Humans , Ligands , Models, Molecular , Molecular Dynamics Simulation , Oligopeptides/chemistry , Oligopeptides/pharmacology , Pandemics , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Sequence Alignment , Structural Homology, Protein , User-Computer Interface , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics
16.
Infect Genet Evol ; 84: 104389, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-459162

ABSTRACT

The newly identified SARS-CoV-2 has now been reported from around 185 countries with more than a million confirmed human cases including more than 120,000 deaths. The genomes of SARS-COV-2 strains isolated from different parts of the world are now available and the unique features of constituent genes and proteins need to be explored to understand the biology of the virus. Spike glycoprotein is one of the major targets to be explored because of its role during the entry of coronaviruses into host cells. We analyzed 320 whole-genome sequences and 320 spike protein sequences of SARS-CoV-2 using multiple sequence alignment. In this study, 483 unique variations have been identified among the genomes of SARS-CoV-2 including 25 nonsynonymous mutations and one deletion in the spike (S) protein. Among the 26 variations detected in S, 12 variations were located at the N-terminal domain (NTD) and 6 variations at the receptor-binding domain (RBD) which might alter the interaction of S protein with the host receptor angiotensin-converting enzyme 2 (ACE2). Besides, 22 amino acid insertions were identified in the spike protein of SARS-CoV-2 in comparison with that of SARS-CoV. Phylogenetic analyses of spike protein revealed that Bat coronavirus have a close evolutionary relationship with circulating SARS-CoV-2. The genetic variation analysis data presented in this study can help a better understanding of SARS-CoV-2 pathogenesis. Based on results reported herein, potential inhibitors against S protein can be designed by considering these variations and their impact on protein structure.


Subject(s)
Alphacoronavirus/genetics , Betacoronavirus/genetics , Genome, Viral , Peptidyl-Dipeptidase A/chemistry , SARS Virus/genetics , Spike Glycoprotein, Coronavirus/chemistry , Alphacoronavirus/classification , Alphacoronavirus/metabolism , Angiotensin-Converting Enzyme 2 , Animals , Base Sequence , Betacoronavirus/classification , Betacoronavirus/metabolism , Binding Sites , Chiroptera/virology , Gene Expression , Humans , Models, Molecular , Mutation , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS Virus/classification , SARS Virus/metabolism , SARS-CoV-2 , Sequence Alignment , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Structural Homology, Protein , Virus Attachment
17.
Biomed Res Int ; 2020: 4389089, 2020.
Article in English | MEDLINE | ID: covidwho-618728

ABSTRACT

The Coronavirus Disease 2019 (COVID-19) is a new viral infection caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2). Genomic analyses have revealed that SARS-CoV-2 is related to Pangolin and Bat coronaviruses. In this report, a structural comparison between the Sars-CoV-2 Envelope and Membrane proteins from different human isolates with homologous proteins from closely related viruses is described. The analyses here reported show the high structural similarity of Envelope and Membrane proteins to the counterparts from Pangolin and Bat coronavirus isolates. However, the comparisons have also highlighted structural differences specific of Sars-CoV-2 proteins which may be correlated to the cross-species transmission and/or to the properties of the virus. Structural modelling has been applied to map the variant sites onto the predicted three-dimensional structure of the Envelope and Membrane proteins.


Subject(s)
Betacoronavirus/chemistry , Coronavirus Infections/virology , Pneumonia, Viral/virology , Viral Envelope Proteins/chemistry , Viral Matrix Proteins/chemistry , Alphacoronavirus/chemistry , Alphacoronavirus/classification , Alphacoronavirus/genetics , Amino Acid Sequence , Animals , Betacoronavirus/classification , Betacoronavirus/genetics , COVID-19 , Chiroptera/virology , Coronaviridae/chemistry , Coronaviridae/classification , Coronaviridae/genetics , Coronavirus Envelope Proteins , Eutheria/virology , Humans , Models, Molecular , Pandemics , Protein Conformation , SARS-CoV-2 , Sequence Homology, Amino Acid , Species Specificity , Structural Homology, Protein , Viral Envelope Proteins/genetics , Viral Matrix Proteins/genetics
18.
Molecules ; 25(11)2020 May 29.
Article in English | MEDLINE | ID: covidwho-436971

ABSTRACT

The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has 79.5% sequence identity with SARS-CoV-1 and the same strategy for host cell invasion through the ACE-2 surface protein. Since the development of novel drugs is a long-lasting process, researchers look for effective substances among drugs already approved or developed for other purposes. The 3D structure of the SARS-CoV-2 main protease was compared with the 3D structures of seven proteases, which are drug targets, and docking analysis to the SARS-CoV-2 protease structure of thirty four approved and on-trial protease inhibitors was performed. Increased 3D structural similarity between the SARS-CoV-2 main protease, the HCV protease and α-thrombin was found. According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than -8.00 kcal/mol and better prediction results than reference compounds. Since some of the compounds are well-tolerated drugs, the promising in silico results may warrant further evaluation for viral anticipation. DPP-4 inhibitors with anti-viral action may be more useful for infected patients with diabetes, while anti-coagulant treatment is proposed in severe SARS-CoV-2 induced pneumonia.


Subject(s)
Anticoagulants/chemistry , Antiviral Agents/chemistry , Betacoronavirus/drug effects , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Amino Acid Sequence , Anticoagulants/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/enzymology , Betacoronavirus/genetics , Binding Sites , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/genetics , Cysteine Endopeptidases/metabolism , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Factor Xa/chemistry , Factor Xa/genetics , Factor Xa/metabolism , Hepacivirus/chemistry , Hepacivirus/enzymology , Hepacivirus/genetics , Humans , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/drug therapy , Protease Inhibitors/pharmacology , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , SARS-CoV-2 , Sequence Alignment , Structural Homology, Protein , Substrate Specificity , Thermodynamics , Thrombin/antagonists & inhibitors , Thrombin/chemistry , Thrombin/genetics , Thrombin/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
19.
Travel Med Infect Dis ; 35: 101646, 2020.
Article in English | MEDLINE | ID: covidwho-47222

ABSTRACT

BACKGROUND: The COVID-19 has now been declared a global pandemic by the World Health Organization. There is an emergent need to search for possible medications. METHOD: Utilization of the available sequence information, homology modeling, and in slico docking a number of available medications might prove to be effective in inhibiting the SARS-CoV-2 two main drug targets, the spike glycoprotein, and the 3CL protease. RESULTS: Several compounds were determined from the in silico docking models that might prove to be effective inhibitors for SARS-CoV-2. Several antiviral medications: Zanamivir, Indinavir, Saquinavir, and Remdesivir show potential as and 3CLPRO main proteinase inhibitors and as a treatment for COVID-19. CONCLUSION: Zanamivir, Indinavir, Saquinavir, and Remdesivir are among the exciting hits on the 3CLPRO main proteinase. It is also exciting to uncover that Flavin Adenine Dinucleotide (FAD) Adeflavin, B2 deficiency medicine, and Coenzyme A, a coenzyme, may also be potentially used for the treatment of SARS-CoV-2 infections. The use of these off-label medications may be beneficial in the treatment of the COVID-19.


Subject(s)
Betacoronavirus/chemistry , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Drug Discovery/methods , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/chemistry , Viral Nonstructural Proteins/chemistry , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/therapeutic use , Binding Sites , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/therapeutic use , Humans , Indinavir/chemistry , Indinavir/therapeutic use , Molecular Docking Simulation , Off-Label Use , Pandemics , Pneumonia, Viral/drug therapy , SARS-CoV-2 , Saquinavir/chemistry , Saquinavir/therapeutic use , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Structural Homology, Protein , Viral Nonstructural Proteins/antagonists & inhibitors , Zanamivir/chemistry , Zanamivir/therapeutic use
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