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1.
Int Immunopharmacol ; 86: 106760, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-634138

ABSTRACT

Due to the vastness of the science virology, it is no longer an offshoot solely of the microbiology. Viruses have become as the causative agents of major epidemics throughout history. Many therapeutic strategies have been used for these microorganisms, and in this way the recognizing of potential targets of viruses is of particular importance for success. For decades, antibodies and antibody fragments have occupied a significant body of the treatment approaches against infectious diseases. Because of their high affinity, they can be designed and engineered against a variety of purposes, mainly since antibody fragments such as scFv, nanobody, diabody, and bispecific antibody have emerged owing to their small size and interesting properties. In this review, we have discussed the antibody discovery and molecular and biological design of antibody fragments as inspiring therapeutic and diagnostic agents against viral targets.


Subject(s)
Antibodies, Viral/therapeutic use , Betacoronavirus/immunology , Biological Products/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Antibodies, Bispecific/immunology , Antibodies, Bispecific/therapeutic use , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/immunology , Biological Products/immunology , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Models, Animal , Drug Design , Drug Discovery , Humans , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Single-Domain Antibodies/immunology , Single-Domain Antibodies/therapeutic use
2.
Nano Lett ; 20(7): 5367-5375, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-628240

ABSTRACT

Geometry-matching has been known to benefit the formation of stable biological interactions in natural systems. Herein, we report that the spiky nanostructures with matched topography to the influenza A virus (IAV) virions could be used to design next-generation advanced virus inhibitors. We demonstrated that nanostructures with spikes between 5 and 10 nm bind significantly better to virions than smooth nanoparticles, due to the short spikes inserting into the gaps of glycoproteins of the IAV virion. Furthermore, an erythrocyte membrane (EM) was coated to target the IAV, and the obtained EM-coated nanostructures could efficiently prevent IAV virion binding to the cells and inhibit subsequent infection. In a postinfection study, the EM-coated nanostructures reduced >99.9% virus replication at the cellular nontoxic dosage. We predict that such a combination of geometry-matching topography and cellular membrane coating will also push forward the development of nanoinhibitors for other virus strains, including SARS-CoV-2.


Subject(s)
Betacoronavirus/ultrastructure , Coronavirus Infections/virology , Nanostructures/ultrastructure , Pneumonia, Viral/virology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Binding Sites , Coronavirus Infections/drug therapy , Drug Design , Humans , Influenza A virus/drug effects , Influenza A virus/ultrastructure , Microscopy, Electron , Models, Biological , Nanotechnology , Pandemics , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/drug effects , Spike Glycoprotein, Coronavirus/ultrastructure , Virus Internalization/drug effects
3.
MAbs ; 12(1): 1804241, 2020.
Article in English | MEDLINE | ID: covidwho-720912

ABSTRACT

In the absence of a proven effective vaccine preventing infection by SARS-CoV-2, or a proven drug to treat COVID-19, the positive results of passive immune therapy using convalescent serum provide a strong lead. We have developed a new class of tetravalent, biparatopic therapy, 89C8-ACE2. It combines the specificity of a monoclonal antibody (89C8) that recognizes the relatively conserved N-terminal domain of the viral Spike (S) glycoprotein, and the ectodomain of ACE2, which binds to the receptor-binding domain of S. This molecule shows exceptional performance in vitro, inhibiting the interaction of recombinant S1 to ACE2 and transduction of ACE2-overexpressing cells by S-pseudotyped lentivirus with IC50s substantially below 100 pM, and with potency approximately 100-fold greater than ACE2-Fc itself. Moreover, 89C8-ACE2 was able to neutralize authentic viral infection in a standard 96-h co-incubation assay at low nanomolar concentrations, making this class of molecule a promising lead for therapeutic applications.


Subject(s)
Antibodies, Neutralizing/pharmacology , Antibodies, Viral/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections , Pandemics , Peptidyl-Dipeptidase A/drug effects , Pneumonia, Viral , Antibodies, Monoclonal/pharmacology , Drug Design , Drug Discovery , Humans , Recombinant Proteins , Spike Glycoprotein, Coronavirus/drug effects
4.
Nat Commun ; 11(1): 4081, 2020 08 14.
Article in English | MEDLINE | ID: covidwho-717117

ABSTRACT

The unprecedented coronavirus disease 2019 (COVID-19) epidemic has created a worldwide public health emergency, and there is an urgent need to develop an effective vaccine to control this severe infectious disease. Here, we find that a single vaccination with a replication-defective human type 5 adenovirus encoding the SARS-CoV-2 spike protein (Ad5-nCoV) protect mice completely against mouse-adapted SARS-CoV-2 infection in the upper and lower respiratory tracts. Additionally, a single vaccination with Ad5-nCoV protects ferrets from wild-type SARS-CoV-2 infection in the upper respiratory tract. This study suggests that the mucosal vaccination may provide a desirable protective efficacy and this delivery mode is worth further investigation in human clinical trials.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , Animals , Antibodies, Viral/immunology , Coronavirus Infections/immunology , Disease Models, Animal , Drug Design , Female , Genetic Vectors , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/administration & dosage , Viral Vaccines/genetics
5.
J Chem Inf Model ; 60(8): 3910-3934, 2020 08 24.
Article in English | MEDLINE | ID: covidwho-714258

ABSTRACT

Protein-protein interactions (PPIs) are attractive targets for drug design because of their essential role in numerous cellular processes and disease pathways. However, in general, PPIs display exposed binding pockets at the interface, and as such, have been largely unexploited for therapeutic interventions with low-molecular weight compounds. Here, we used docking and various rescoring strategies in an attempt to recover PPI inhibitors from a set of active and inactive molecules for 11 targets collected in ChEMBL and PubChem. Our focus is on the screening power of the various developed protocols and on using fast approaches so as to be able to apply such a strategy to the screening of ultralarge libraries in the future. First, we docked compounds into each target using the fast "pscreen" mode of the structure-based virtual screening (VS) package Surflex. Subsequently, the docking poses were postprocessed to derive a set of 3D topological descriptors: (i) shape similarity and (ii) interaction fingerprint similarity with a co-crystallized inhibitor, (iii) solvent-accessible surface area, and (iv) extent of deviation from the geometric center of a reference inhibitor. The derivatized descriptors, together with descriptor-scaled scoring functions, were utilized to investigate possible impacts on VS performance metrics. Moreover, four standalone scoring functions, RF-Score-VS (machine-learning), DLIGAND2 (knowledge-based), Vinardo (empirical), and X-SCORE (empirical), were employed to rescore the PPI compounds. Collectively, the results indicate that the topological scoring algorithms could be valuable both at a global level, with up to 79% increase in areas under the receiver operating characteristic curve for some targets, and in early stages, with up to a 4-fold increase in enrichment factors at 1% of the screened collections. Outstandingly, DLIGAND2 emerged as the best scoring function on this data set, outperforming all rescoring techniques in terms of VS metrics. The described methodology could help in the rational design of small-molecule PPI inhibitors and has direct applications in many therapeutic areas, including cancer, CNS, and infectious diseases such as COVID-19.


Subject(s)
Drug Design , Drug Discovery , Protein Interaction Maps/drug effects , Small Molecule Libraries/pharmacology , Algorithms , Betacoronavirus/drug effects , Betacoronavirus/metabolism , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Databases, Protein , Humans , Ligands , Machine Learning , Molecular Docking Simulation , Molecular Targeted Therapy , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Proteins/chemistry , Proteins/metabolism , Small Molecule Libraries/chemistry
6.
Mol Syst Biol ; 16(7): e9628, 2020 07.
Article in English | MEDLINE | ID: covidwho-707164

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 has is a global health challenge. Angiotensin-converting enzyme 2 (ACE2) is the host receptor for SARS-CoV-2 entry. Recent studies have suggested that patients with hypertension and diabetes treated with ACE inhibitors (ACEIs) or angiotensin receptor blockers have a higher risk of COVID-19 infection as these drugs could upregulate ACE2, motivating the study of ACE2 modulation by drugs in current clinical use. Here, we mined published datasets to determine the effects of hundreds of clinically approved drugs on ACE2 expression. We find that ACEIs are enriched for ACE2-upregulating drugs, while antineoplastic agents are enriched for ACE2-downregulating drugs. Vorinostat and isotretinoin are the top ACE2 up/downregulators, respectively, in cell lines. Dexamethasone, a corticosteroid used in treating severe acute respiratory syndrome and COVID-19, significantly upregulates ACE2 both in vitro and in vivo. Further top ACE2 regulators in vivo or in primary cells include erlotinib and bleomycin in the lung and vancomycin, cisplatin, and probenecid in the kidney. Our study provides leads for future work studying ACE2 expression modulators.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , A549 Cells , Betacoronavirus , Bleomycin/pharmacology , Dexamethasone/pharmacology , Drug Design , Drug Evaluation, Preclinical , Erlotinib Hydrochloride/pharmacology , Fluphenazine/pharmacology , HEK293 Cells , Humans , Kidney/drug effects , Lung/drug effects , MCF-7 Cells , Pandemics , Peptidyl-Dipeptidase A , Systems Biology , Up-Regulation , Vemurafenib/pharmacology
7.
ACS Nano ; 14(8): 10616-10623, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-696515

ABSTRACT

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein plays a crucial role in binding the human cell receptor ACE2 that is required for viral entry. Many studies have been conducted to target the structures of RBD-ACE2 binding and to design RBD-targeting vaccines and drugs. Nevertheless, mutations distal from the SARS-CoV-2 RBD also impact its transmissibility and antibody can target non-RBD regions, suggesting the incomplete role of the RBD region in the spike protein-ACE2 binding. Here, in order to elucidate distant binding mechanisms, we analyze complexes of ACE2 with the wild-type spike protein and with key mutants via large-scale all-atom explicit solvent molecular dynamics simulations. We find that though distributed approximately 10 nm away from the RBD, the SARS-CoV-2 polybasic cleavage sites enhance, via electrostatic interactions and hydration, the RBD-ACE2 binding affinity. A negatively charged tetrapeptide (GluGluLeuGlu) is then designed to neutralize the positively charged arginine on the polybasic cleavage sites. We find that the tetrapeptide GluGluLeuGlu binds to one of the three polybasic cleavage sites of the SARS-CoV-2 spike protein lessening by 34% the RBD-ACE2 binding strength. This significant binding energy reduction demonstrates the feasibility to neutralize RBD-ACE2 binding by targeting this specific polybasic cleavage site. Our work enhances understanding of the binding mechanism of SARS-CoV-2 to ACE2, which may aid the design of therapeutics for COVID-19 infection.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Substitution , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/genetics , Binding Sites/genetics , Drug Design , Host Microbial Interactions/drug effects , Humans , Molecular Dynamics Simulation , Mutation , Oligopeptides/chemistry , Oligopeptides/pharmacology , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/genetics , Protein Binding/drug effects , Protein Binding/genetics , Protein Binding/physiology , Protein Domains , Receptors, Virus/chemistry , Receptors, Virus/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Virus Internalization
8.
F1000Res ; 9: 663, 2020.
Article in English | MEDLINE | ID: covidwho-695359

ABSTRACT

Background: Human coronavirus (SARS-CoV-2) is causing a pandemic with significant morbidity and mortality. As no effective novel drugs are available currently, drug repurposing is an alternative intervention strategy. Here we present an  in silico drug repurposing study that implements successful concepts of computer-aided drug design (CADD) technology for repurposing known drugs to interfere with viral cellular entry via the spike glycoprotein (SARS-CoV-2-S), which mediates host cell entry via the hACE2 receptor. Methods: A total of 4015 known and approved small molecules were screened for interaction with SARS-CoV-2-S through docking studies and 15 lead molecules were shortlisted. Additionally, streptomycin, ciprofloxacin, and glycyrrhizic acid (GA) were selected based on their reported anti-viral activity, safety, availability and affordability. The 18 molecules were subjected to molecular dynamics (MD) simulation. Results: The MD simulation results indicate that GA of plant origin may be repurposed for SARS-CoV-2 intervention, pending further studies. Conclusions: Repurposing is a beneficial strategy for treating COVID-19 with existing drugs. It is aimed at using docking studies to screen molecules for clinical application and investigating their efficacy in inhibiting SARS-CoV-2-S. SARS-CoV-2-S is a key pathogenic protein that mediates pathogen-host interaction. Hence, the molecules screened for inhibitory properties against SARS-CoV-2-S can be clinically used to treat COVID-19 since the safety profile is already known.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections , Drug Design , Drug Repositioning , Pandemics , Pneumonia, Viral , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Humans , Molecular Docking Simulation , Peptidyl-Dipeptidase A , Virus Internalization/drug effects
9.
J Enzyme Inhib Med Chem ; 35(1): 1539-1544, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-694175

ABSTRACT

Coronavirus disease 2019 (COVID-19) has been a pandemic disease of which the termination is not yet predictable. Currently, researches to develop vaccines and treatments is going on globally to cope with this disastrous disease. Main protease (3CLpro) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the good targets to find antiviral agents before vaccines are available. Some flavonoids are known to inhibit 3CLpro from SARS-CoV which causes SARS. Since their sequence identity is 96%, a similar approach was performed with a flavonoid library. Baicalin, herbacetin, and pectolinarin have been discovered to block the proteolytic activity of SARS-CoV-2 3CLpro. An in silico docking study showed that the binding modes of herbacetin and pectolinarin are similar to those obtained from the catalytic domain of SARS-CoV 3CLpro. However, their binding affinities are different due to the usage of whole SARS-CoV-2 3CLpro in this study. Baicalin showed an effective inhibitory activity against SARS-CoV-2 3CLpro and its docking mode is different from those of herbacetin and pectolinarin. This study suggests important scaffolds to design 3CLpro inhibitors to develop antiviral agents or health-foods and dietary supplements to cope with SARS-CoV-2.


Subject(s)
Coronavirus Infections/drug therapy , Flavonoids/chemistry , Pneumonia, Viral/drug therapy , Viral Proteins/antagonists & inhibitors , Viral Proteins/chemistry , Antiviral Agents/chemistry , Betacoronavirus , Drug Design , Fluorescence Resonance Energy Transfer , Humans , Molecular Docking Simulation , Pandemics , Protease Inhibitors/chemistry , Protein Binding , Protein Conformation , Spectrophotometry , Tryptophan/chemistry
10.
Int J Mol Sci ; 21(12)2020 Jun 26.
Article in English | MEDLINE | ID: covidwho-692289

ABSTRACT

In the 21st century, three highly pathogenic betacoronaviruses have emerged, with an alarming rate of human morbidity and case fatality. Genomic information has been widely used to understand the pathogenesis, animal origin and mode of transmission of coronaviruses in the aftermath of the 2002-2003 severe acute respiratory syndrome (SARS) and 2012 Middle East respiratory syndrome (MERS) outbreaks. Furthermore, genome sequencing and bioinformatic analysis have had an unprecedented relevance in the battle against the 2019-2020 coronavirus disease 2019 (COVID-19) pandemic, the newest and most devastating outbreak caused by a coronavirus in the history of mankind. Here, we review how genomic information has been used to tackle outbreaks caused by emerging, highly pathogenic, betacoronavirus strains, emphasizing on SARS-CoV, MERS-CoV and SARS-CoV-2. We focus on shared genomic features of the betacoronaviruses and the application of genomic information to phylogenetic analysis, molecular epidemiology and the design of diagnostic systems, potential drugs and vaccine candidates.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/virology , Genome, Viral , Pandemics/prevention & control , Pneumonia, Viral/virology , Animals , Betacoronavirus/immunology , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Drug Design , Genes, Viral , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Molecular Epidemiology , Phylogeny , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , SARS Virus/genetics , Severe Acute Respiratory Syndrome/virology , Viral Vaccines/genetics , Viral Vaccines/immunology
12.
Infect Dis Poverty ; 9(1): 88, 2020 Jul 10.
Article in English | MEDLINE | ID: covidwho-690345

ABSTRACT

BACKGROUND: An outbreak of infection caused by SARS-CoV-2 recently has brought a great challenge to public health. Rapid identification of immune epitopes would be an efficient way to screen the candidates for vaccine development at the time of pandemic. This study aimed to predict the protective epitopes with bioinformatics methods and resources for vaccine development. METHODS: The genome sequence and protein sequences of SARS-CoV-2 were retrieved from the National Center for Biotechnology Information (NCBI) database. ABCpred and BepiPred servers were utilized for sequential B-cell epitope analysis. Discontinuous B-cell epitopes were predicted via DiscoTope 2.0 program. IEDB server was utilized for HLA-1 and HLA-2 binding peptides computation. Surface accessibility, antigenicity, and other important features of forecasted epitopes were characterized for immunogen potential evaluation. RESULTS: A total of 63 sequential B-cell epitopes on spike protein were predicted and 4 peptides (Spike315-324, Spike333-338, Spike648-663, Spike1064-1079) exhibited high antigenicity score and good surface accessibility. Ten residues within spike protein (Gly496, Glu498, Pro499, Thr500, Leu1141, Gln1142, Pro1143, Glu1144, Leu1145, Asp1146) are forecasted as components of discontinuous B-cell epitopes. The bioinformatics analysis of HLA binding peptides within nucleocapsid protein produced 81 and 64 peptides being able to bind MHC class I and MHC class II molecules respectively. The peptides (Nucleocapsid66-75, Nucleocapsid104-112) were predicted to bind a wide spectrum of both HLA-1 and HLA-2 molecules. CONCLUSIONS: B-cell epitopes on spike protein and T-cell epitopes within nucleocapsid protein were identified and recommended for developing a protective vaccine against SARS-CoV-2.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/immunology , Computational Biology/methods , Coronavirus Infections/prevention & control , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , Amino Acid Sequence , Coronavirus Infections/immunology , Coronavirus Infections/virology , Drug Design , Epitopes, B-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/chemistry , Humans , Immunogenicity, Vaccine/immunology , Models, Molecular , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Sequence Alignment , Sequence Analysis , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Viral Envelope Proteins/immunology
13.
Sci Rep ; 10(1): 12493, 2020 07 27.
Article in English | MEDLINE | ID: covidwho-689152

ABSTRACT

The number of cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) has reached over 114,000. SARS-CoV-2 caused a pandemic in Wuhan, China, in December 2019 and is rapidly spreading globally. It has been reported that peptide-like anti-HIV-1 drugs are effective against SARS-CoV Main protease (Mpro). Due to the close phylogenetic relationship between SARS-CoV and SARS-CoV-2, their main proteases share many structural and functional features. Thus, these drugs are also regarded as potential drug candidates targeting SARS-CoV-2 Mpro. However, the mechanism of action of SARS-CoV-2 Mpro at the atomic-level is unknown. In the present study, we revealed key interactions between SARS-CoV-2 Mpro and three drug candidates by performing pharmacophore modeling and 1 µs molecular dynamics (MD) simulations. His41, Gly143, and Glu166 formed interactions with the functional groups that were common among peptide-like inhibitors in all MD simulations. These interactions are important targets for potential drugs against SARS-CoV-2 Mpro.


Subject(s)
Betacoronavirus/metabolism , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Amino Acid Sequence , Betacoronavirus/chemistry , Betacoronavirus/isolation & purification , Binding Sites , Coronavirus Infections/pathology , Coronavirus Infections/virology , Drug Design , Humans , Molecular Dynamics Simulation , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protease Inhibitors/metabolism , Protein Structure, Tertiary , SARS Virus/chemistry , SARS Virus/isolation & purification , SARS Virus/metabolism , Sequence Alignment , Viral Nonstructural Proteins/metabolism
14.
J Theor Biol ; 505: 110425, 2020 11 21.
Article in English | MEDLINE | ID: covidwho-680417

ABSTRACT

The interaction between the angiotensin-converting enzyme 2 (ACE2) and the receptor binding domain (RBD) of the spike protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a pivotal role in virus entry into the host cells. Since recombinant ACE2 protein has been suggested as an anti-SARS-CoV-2 therapeutic agent, this study was conducted to design an ACE2 protein with more desirable properties. In this regard, the amino acids with central roles in enzymatic activity of the ACE2 were substituted. Moreover, saturation mutagenesis at the interaction interface between the ACE2 and RBD was performed to increase their interaction affinity. The best mutations to increase the structural and thermal stability of the ACE2 were also selected based on B factors and mutation effects. The obtained resulted revealed that the Arg273Gln and Thr445Gly mutation have drastically reduced the binding affinity of the angiotensin-II into the active site of ACE2. The Thr27Arg mutation was determined to be the most potent mutation to increase the binding affinity. The Asp427Arg mutation was done to decrease the flexibility of the region with high B factor. The Pro451Met mutation along with the Gly448Trp mutation was predicted to increase the thermodynamic stability and thermostability of the ACE2. The designed therapeutic ACE2 would have no enzymatic activity while it could bear stronger interaction with Spike glycoprotein of the SARS-CoV-2. Moreover, decreased in vivo enzymatic degradation would be anticipated due to increased thermostability. This engineered ACE2 could be exploited as a novel therapeutic agent against COVID-19 after necessary evaluations.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/drug therapy , Drug Design , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Protein Engineering/methods , Amino Acid Substitution , Betacoronavirus/genetics , Binding Sites , Directed Molecular Evolution , Humans , Pandemics , Peptidyl-Dipeptidase A/therapeutic use , Protein Binding , Protein Interaction Domains and Motifs/genetics , Protein Stability , Spike Glycoprotein, Coronavirus/metabolism
15.
Molecules ; 25(14)2020 Jul 13.
Article in English | MEDLINE | ID: covidwho-646769

ABSTRACT

We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CLpro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CLpro enzyme of the closely related SARS-CoV virus. The top-ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CLpro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CLpro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CLpro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.


Subject(s)
Betacoronavirus/enzymology , Coronavirus Infections/drug therapy , Drug Discovery , Pneumonia, Viral/drug therapy , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Binding Sites , Computer Simulation , Cysteine Endopeptidases , Drug Design , Humans , Inhibitory Concentration 50 , Ligands , Models, Molecular , Molecular Structure , Pandemics , Software , Thermodynamics
16.
Theranostics ; 10(16): 7150-7162, 2020.
Article in English | MEDLINE | ID: covidwho-639991

ABSTRACT

In December 2019, a new coronavirus disease (COVID-19) outbreak occurred in Wuhan, China. Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which is the seventh coronavirus known to infect humans, is highly contagious and has rapidly expanded worldwide since its discovery. Quantitative nucleic acid testing has become the gold standard for diagnosis and guiding clinical decisions regarding the use of antiviral therapy. However, the RT-qPCR assays targeting SARS-CoV-2 have a number of challenges, especially in terms of primer design. Primers are the pivotal components of a RT-qPCR assay. Once virus mutation and recombination occur, it is difficult to effectively diagnose viral infection by existing RT-qPCR primers. Some primers and probes have also been made available on the WHO website for reference. However, no previous review has systematically compared the previously reported primers and probes and described how to design new primers in the event of a new coronavirus infection. This review focuses on how primers and probes can be designed methodically and rationally, and how the sensitivity and specificity of the detection process can be improved. This brief review will be useful for the accurate diagnosis and timely treatment of the new coronavirus pneumonia.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , RNA, Viral/genetics , RNA/genetics , Real-Time Polymerase Chain Reaction/methods , Base Sequence , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Drug Design , Genes, Viral , Humans , Nucleic Acid Conformation , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , RNA/chemistry , RNA Probes/genetics , RNA, Viral/chemistry , Real-Time Polymerase Chain Reaction/statistics & numerical data , Sensitivity and Specificity , Theranostic Nanomedicine
17.
J Struct Biol ; 211(3): 107575, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-640251

ABSTRACT

COVID-19 is a respiratory disease caused by the coronavirus SARS-CoV-2. SARS-CoV-2 has many similarities with SARS-CoV. Both viruses rely on a protease called the main protease, or Mpro, for replication. Therefore, inhibiting Mpro may be a successful strategy for treating COVID-19. Structures of the main proteases of SARS-CoV and SARS-CoV-2 with and without inhibitor N3 are available in the Protein Data Bank. Comparing these structures revealed residue interaction network changes associated with N3 inhibition. Comparing network clustering with and without inhibitor N3 identified the formation of a cluster of residues 17, 18, 30-33, 70, 95, 98, 103, 117, 122, and 177 as a network change in both viral proteases when bound to inhibitor N3. Betweenness and stress centrality differences as well as differences in bond energies and relative B-factors when comparing free Mpro to inhibitor-bound Mpro identified residues 131, 175, 182, and 185 as possibly conformationally relevant when bound to the inhibitor N3. Taken together, these results provide insight into conformational changes of betacoronavirus Mpros when bound to an inhibitor.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/enzymology , Enzyme Inhibitors/pharmacology , SARS Virus/enzymology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Catalytic Domain , Cluster Analysis , Coronavirus Infections/drug therapy , Cysteine Endopeptidases , Drug Design , Humans , Pandemics , Pneumonia, Viral/drug therapy , Protein Binding
18.
Chaos ; 30(6): 061102, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-628595

ABSTRACT

There is an urgent necessity of effective medication against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), which is producing the COVID-19 pandemic across the world. Its main protease (Mpro) represents an attractive pharmacological target due to its involvement in essential viral functions. The crystal structure of free Mpro shows a large structural resemblance with the main protease of SARS CoV (nowadays known as SARS CoV-1). Here, we report that average SARS CoV-2 Mpro is 1900% more sensitive than SARS CoV-1 Mpro in transmitting tiny structural changes across the whole protein through long-range interactions. The largest sensitivity of Mpro to structural perturbations is located exactly around the catalytic site Cys-145 and coincides with the binding site of strong inhibitors. These findings, based on a simplified representation of the protein as a residue network, may help in designing potent inhibitors of SARS CoV-2 Mpro.


Subject(s)
Betacoronavirus/metabolism , Catalytic Domain/drug effects , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/metabolism , Pneumonia, Viral/drug therapy , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/metabolism , Amino Acid Sequence , Binding Sites/drug effects , Crystallography, X-Ray , Cysteine Endopeptidases/drug effects , Drug Design , Humans , Pandemics , SARS Virus/metabolism , Viral Nonstructural Proteins/drug effects
19.
Biomed Pharmacother ; 129: 110493, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-626324

ABSTRACT

Despite intense research there is currently no effective vaccine available against the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in the later 2019 and responsible for the COVID-19 pandemic. This infectious and communicable disease has become one of the major public health challenges in the world. The clinical management of COVID-19 has been limited to infection prevention and control measures associated with supportive care such as supplemental oxygen and mechanical ventilation. Meanwhile efforts to find an effective treatment to inhibit virus replication, mitigate the symptoms, increase survival and decrease mortality rate are ongoing. Several classes of drugs, many of them already in use for other diseases, are being evaluated based on the body of clinical knowledge obtained from infected patients regarding to the natural history and evolution of the infection. Herein we will provide an updated overview of the natural history and current knowledge on drugs and therapeutic agents being tested for the prevention and treatment of COVID-19. These include different classes of drugs such as antiviral agents (chloroquine, ivermectin, nitazoxanide, hydroxychloroquine, lopinavir, remdesivir, tocilizumab), supporting agents (Vitamin C, Vitamin D, azithromycin, corticosteroids) and promising investigational vaccines. Considering the controversies and excessive number of compounds being tested and reported in the literature we hope that this review can provide useful and updated consolidated information on potential drugs used to prevent, control and treat COVID-19 patients worldwide.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Betacoronavirus/drug effects , Betacoronavirus/isolation & purification , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Drug Design , Humans , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Public Health , Viral Vaccines/administration & dosage
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