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1.
Sci Rep ; 10(1): 22200, 2020 12 17.
Article in English | MEDLINE | ID: covidwho-1493197

ABSTRACT

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is responsible for the novel coronavirus disease 2019 (COVID-19). An appealing antiviral drug target is the coronavirus 3C-like protease (3CLpro) that is responsible for the processing of the viral polyproteins and liberation of functional proteins essential for the maturation and infectivity of the virus. In this study, multiple thermal analytical techniques have been implemented to acquire the thermodynamic parameters of 3CLpro at different buffer conditions. 3CLpro exhibited relatively high thermodynamic stabilities over a wide pH range; however, the protease was found to be less stable in the presence of salts. Divalent metal cations reduced the thermodynamic stability of 3CLpro more than monovalent cations; however, altering the ionic strength of the buffer solution did not alter the stability of 3CLpro. Furthermore, the most stable thermal kinetic stability of 3CLpro was recorded at pH 7.5, with the highest enthalpy of activation calculated from the slope of Eyring plot. The biochemical and biophysical properties of 3CLpro explored here may improve the solubility and stability of 3CLpro for optimum conditions for the setup of an enzymatic assay for the screening of inhibitors to be used as lead candidates in the discovery of drugs and design of antiviral therapeutics against COVID-19.


Subject(s)
COVID-19/virology , Chymases/metabolism , Coronavirus 3C Proteases/metabolism , Peptide Hydrolases/metabolism , SARS-CoV-2/metabolism , Antiviral Agents/therapeutic use , Humans , Hydrogen-Ion Concentration , Protease Inhibitors/therapeutic use , Thermodynamics
2.
Molecules ; 26(20)2021 Oct 14.
Article in English | MEDLINE | ID: covidwho-1470936

ABSTRACT

The SARS-CoV-2 virus is highly contagious to humans and has caused a pandemic of global proportions. Despite worldwide research efforts, efficient targeted therapies against the virus are still lacking. With the ready availability of the macromolecular structures of coronavirus and its known variants, the search for anti-SARS-CoV-2 therapeutics through in silico analysis has become a highly promising field of research. In this study, we investigate the inhibiting potentialities of triazole-based compounds against the SARS-CoV-2 main protease (Mpro). The SARS-CoV-2 main protease (Mpro) is known to play a prominent role in the processing of polyproteins that are translated from the viral RNA. Compounds were pre-screened from 171 candidates (collected from the DrugBank database). The results showed that four candidates (Bemcentinib, Bisoctrizole, PYIITM, and NIPFC) had high binding affinity values and had the potential to interrupt the main protease (Mpro) activities of the SARS-CoV-2 virus. The pharmacokinetic parameters of these candidates were assessed and through molecular dynamic (MD) simulation their stability, interaction, and conformation were analyzed. In summary, this study identified the most suitable compounds for targeting Mpro, and we recommend using these compounds as potential drug molecules against SARS-CoV-2 after follow up studies.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Triazoles/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Benzocycloheptenes/chemistry , Benzocycloheptenes/metabolism , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Databases, Chemical , Half-Life , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , Protein Binding , Quantitative Structure-Activity Relationship , SARS-CoV-2/isolation & purification , Triazoles/metabolism , Triazoles/therapeutic use
3.
Molecules ; 26(20)2021 Oct 10.
Article in English | MEDLINE | ID: covidwho-1463774

ABSTRACT

A series of novel naphthopyrano[2,3-d]pyrimidin-11(12H)-one containing isoxazole nucleus 4 was synthesized under microwave irradiation and classical conditions in moderate to excellent yields upon 1,3-dipolar cycloaddition reaction using various arylnitrile oxides under copper(I) catalyst. A one-pot, three-component reaction, N-propargylation and Dimroth rearrangement were used as the key steps for the preparation of the dipolarophiles3. The structures of the synthesized compounds were established by 1H NMR, 13C NMR and HRMS-ES means. The present study aims to also predict the theoretical assembly of the COVID-19 protease (SARS-CoV-2 Mpro) and to discover in advance whether this protein can be targeted by the compounds 4a-1 and thus be synthesized. The docking scores of these compounds were compared to those of the co-crystallized native ligand inhibitor (N3) which was used as a reference standard. The results showed that all the synthesized compounds (4a-l) gave interesting binding scores compared to those of N3 inhibitor. It was found that compounds 4a, 4e and 4i achieved greatly similar binding scores and modes of interaction than N3, indicating promising affinity towards SARS-CoV-2 Mpro. On the other hand, the derivatives 4k, 4h and 4j showed binding energy scores (-8.9, -8.5 and -8.4 kcal/mol, respectively) higher than the Mpro N3 inhibitor (-7.0 kcal/mol), revealing, in their turn, a strong interaction with the target protease, although their interactions were not entirely comparable to that of the reference N3.


Subject(s)
Antiviral Agents/chemical synthesis , Drug Design , Isoxazoles/chemistry , Pyrimidinones/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Click Chemistry , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Humans , Microwaves , Molecular Docking Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , SARS-CoV-2/isolation & purification , Structure-Activity Relationship , Thermodynamics
4.
Int J Mol Sci ; 22(18)2021 Sep 10.
Article in English | MEDLINE | ID: covidwho-1409705

ABSTRACT

The inhibition mechanism of the main protease (Mpro) of SARS-CoV-2 by ebselen (EBS) and its analog with a hydroxyl group at position 2 of the benzisoselenazol-3(2H)-one ring (EBS-OH) was studied by using a density functional level of theory. Preliminary molecular dynamics simulations on the apo form of Mpro were performed taking into account both the hydrogen donor and acceptor natures of the Nδ and Nε of His41, a member of the catalytic dyad. The potential energy surfaces for the formation of the Se-S covalent bond mediated by EBS and EBS-OH on Mpro are discussed in detail. The EBS-OH shows a distinctive behavior with respect to EBS in the formation of the noncovalent complex. Due to the presence of canonical H-bonds and noncanonical ones involving less electronegative atoms, such as sulfur and selenium, the influence on the energy barriers and reaction energy of the Minnesota hybrid meta-GGA functionals M06, M06-2X and M08HX, and the more recent range-separated hybrid functional wB97X were also considered. The knowledge of the inhibition mechanism of Mpro by the small protease inhibitors EBS or EBS-OH can enlarge the possibilities for designing more potent and selective inhibitor-based drugs to be used in combination with other antiviral therapies.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Isoindoles/pharmacology , Organoselenium Compounds/pharmacology , Protease Inhibitors/pharmacology , Antiviral Agents/therapeutic use , Binding Sites/drug effects , COVID-19/virology , Catalytic Domain/drug effects , Coronavirus 3C Proteases/metabolism , Drug Design , Humans , Isoindoles/chemistry , Isoindoles/therapeutic use , Molecular Docking Simulation , Molecular Dynamics Simulation , Organoselenium Compounds/chemistry , Organoselenium Compounds/therapeutic use , Protease Inhibitors/chemistry , Protease Inhibitors/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism
5.
J Pharmacol Exp Ther ; 378(2): 166-172, 2021 08.
Article in English | MEDLINE | ID: covidwho-1403003

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to be a global threat since its emergence. Although several COVID-19 vaccines have become available, the prospective timeframe for achieving effective levels of vaccination across global populations remains uncertain. Moreover, the emergence of SARS-CoV-2 variants presents continuing potential challenges for future vaccination planning. Therefore, development of effective antiviral therapies continues to be an urgent unmet need for COVID-19. Successful antiviral regimens for the treatment of human immunodeficiency virus and hepatitis C virus infections have established viral proteases as validated targets for antiviral drug development. In this context, we review protease targets in drug development, currently available antiviral protease inhibitors, and therapeutic development efforts on SARS-CoV-2 main protease and papain-like protease. SIGNIFICANCE STATEMENT: Coronavirus disease 2019 (COVID-19) continues to be a global threat since its emergence. The development of effective antiviral therapeutics for COVID-19 remains an urgent and long-term need. Because viral proteases are validated drug targets, specific severe acute respiratory syndrome coronavirus 2 protease inhibitors are critical therapeutics to be developed for treatment of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Development , Protease Inhibitors/pharmacology , SARS-CoV-2/enzymology , Viral Proteases/metabolism , Animals , Antiviral Agents/therapeutic use , Humans , Protease Inhibitors/therapeutic use , SARS-CoV-2/drug effects
6.
Eur J Med Chem ; 225: 113818, 2021 Dec 05.
Article in English | MEDLINE | ID: covidwho-1385491

ABSTRACT

Cathepsin C, an important lysosomal cysteine protease, mediates the maturation process of neutrophil serine proteases, and participates in the inflammation and immune regulation process associated with polymorphonuclear neutrophils. Therefore, cathepsin C is considered to be an attractive target for treating inflammatory diseases. With INS1007 (trade name: brensocatib) being granted a breakthrough drug designation by FDA for the treatment of Adult Non-cystic Fibrosis Bronchiectasis and Coronavirus Disease 2019, the development of cathepsin C inhibitor will attract attentions from medicinal chemists in the future soon. Here, we summarized the research results of cathepsin C as a therapeutic target, focusing on the development of cathepsin C inhibitor, and provided guidance and reference opinions for the upcoming development boom of cathepsin C inhibitor.


Subject(s)
Anti-Inflammatory Agents/chemistry , Cathepsin C/antagonists & inhibitors , Drug Discovery , Protease Inhibitors/chemistry , Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Cathepsin C/genetics , Cathepsin C/metabolism , Humans , Papillon-Lefevre Disease/genetics , Papillon-Lefevre Disease/pathology , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/pathology , SARS-CoV-2/isolation & purification , Serine Endopeptidases/metabolism
8.
Int J Mol Sci ; 22(17)2021 Aug 30.
Article in English | MEDLINE | ID: covidwho-1379978

ABSTRACT

The SARS-CoV-2 main protease (Mpro) is one of the molecular targets for drug design. Effective vaccines have been identified as a long-term solution but the rate at which they are being administered is slow in several countries, and mutations of SARS-CoV-2 could render them less effective. Moreover, remdesivir seems to work only with some types of COVID-19 patients. Hence, the continuous investigation of new treatments for this disease is pivotal. This study investigated the inhibitory role of natural products against SARS-CoV-2 Mpro as repurposable agents in the treatment of coronavirus disease 2019 (COVID-19). Through in silico approach, selected flavonoids were docked into the active site of Mpro. The free energies of the ligands complexed with Mpro were computationally estimated using the molecular mechanics-generalized Born surface area (MM/GBSA) method. In addition, the inhibition process of SARS-CoV-2 Mpro with these ligands was simulated at 100 ns in order to uncover the dynamic behavior and complex stability. The docking results showed that the selected flavonoids exhibited good poses in the binding domain of Mpro. The amino acid residues involved in the binding of the selected ligands correlated well with the residues involved with the mechanism-based inhibitor (N3) and the docking score of Quercetin-3-O-Neohesperidoside (-16.8 Kcal/mol) ranked efficiently with this inhibitor (-16.5 Kcal/mol). In addition, single-structure MM/GBSA rescoring method showed that Quercetin-3-O-Neohesperidoside (-87.60 Kcal/mol) is more energetically favored than N3 (-80.88 Kcal/mol) and other ligands (Myricetin 3-Rutinoside (-87.50 Kcal/mol), Quercetin 3-Rhamnoside (-80.17 Kcal/mol), Rutin (-58.98 Kcal/mol), and Myricitrin (-49.22 Kcal/mol). The molecular dynamics simulation (MDs) pinpointed the stability of these complexes over the course of 100 ns with reduced RMSD and RMSF. Based on the docking results and energy calculation, together with the RMSD of 1.98 ± 0.19 Å and RMSF of 1.00 ± 0.51 Å, Quercetin-3-O-Neohesperidoside is a better inhibitor of Mpro compared to N3 and other selected ligands and can be repurposed as a drug candidate for the treatment of COVID-19. In addition, this study demonstrated that in silico docking, free energy calculations, and MDs, respectively, are applicable to estimating the interaction, energetics, and dynamic behavior of molecular targets by natural products and can be used to direct the development of novel target function modulators.


Subject(s)
Biological Products/metabolism , SARS-CoV-2/enzymology , Viral Matrix Proteins/metabolism , Binding Sites , Biological Products/chemistry , Biological Products/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Drug Design , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , Quercetin/analogs & derivatives , Quercetin/chemistry , Quercetin/metabolism , Quercetin/therapeutic use , SARS-CoV-2/isolation & purification , Viral Matrix Proteins/chemistry
9.
Int J Mol Sci ; 22(16)2021 Aug 22.
Article in English | MEDLINE | ID: covidwho-1367851

ABSTRACT

Unfortunately, COVID-19 is still a threat to humankind and has a dramatic impact on human health, social life, the world economy, and food security. With the limited number of suggested therapies under clinical trials, the discovery of novel therapeutic agents is essential. Here, a previously identified anti-SARS-CoV-2 compound named Compound 13 (1,2,5-Oxadiazole-3-carboximidic acid, 4,4'-(methylenediimino) bis,bis[[(2-hydroxyphenyl)methylene]hydrazide) was subjected to an iterated virtual screening against SARS-CoV-2 Mpro using a combination of Ligand Designer and PathFinder. PathFinder, a computational reaction enumeration tool, was used for the rapid generation of enumerated structures via default reaction library. Ligand designer was employed for the computerized lead optimization and selection of the best structural modification that resulted in a favorable ligand-protein complex. The obtained compounds that showed the best binding to Mpro were re-screened against TMPRSS2, leading to the identification of 20 shared compounds. The compounds were further visually inspected, which resulted in the identification of five shared compounds M1-5 with dual binding affinity. In vitro evaluation and enzyme inhibition assay indicated that M3, an analogue of Compound 13 afforded by replacing the phenolic moiety with pyridinyl, possesses an improved antiviral activity and safety. M3 displayed in vitro antiviral activity with IC50 0.016 µM and Mpro inhibition activity with IC50 0.013 µM, 7-fold more potent than the parent Compound 13 and potent than the antivirals drugs that are currently under clinical trials. Moreover, M3 showed potent activity against human TMPRSS2 and furin enzymes with IC50 0.05, and 0.08 µM, respectively. Molecular docking, WaterMap analysis, molecular dynamics simulation, and R-group analysis confirmed the superiority of the binding fit to M3 with the target enzymes. WaterMap analysis calculated the thermodynamic properties of the hydration site in the binding pocket that significantly affects the biological activity. Loading M3 on zinc oxide nanoparticles (ZnO NPs) increased the antiviral activity of the compound 1.5-fold, while maintaining a higher safety profile. In conclusion, lead optimized discovery following an iterated virtual screening in association with molecular docking and biological evaluation revealed a novel compound named M3 with promising dual activity against SARS-CoV-2. The compound deserves further investigation for potential clinical-based studies.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Discovery/methods , Protease Inhibitors/pharmacology , Antiviral Agents/therapeutic use , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Enzyme Assays , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Serine Endopeptidases/metabolism
10.
Biomolecules ; 11(8)2021 08 23.
Article in English | MEDLINE | ID: covidwho-1367768

ABSTRACT

In 2019, COVID-19 emerged as a severe respiratory disease that is caused by the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The disease has been associated with high mortality rate, especially in patients with comorbidities such as diabetes, cardiovascular and kidney diseases. This could be attributed to dysregulated immune responses and severe systemic inflammation in COVID-19 patients. The use of effective antiviral drugs against SARS-CoV-2 and modulation of the immune responses could be a potential therapeutic strategy for COVID-19. Studies have shown that natural phenolic compounds have several pharmacological properties, including anticoronavirus and immunomodulatory activities. Therefore, this review discusses the dual action of these natural products from the perspective of applicability at COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Flavonoids/therapeutic use , Immunologic Factors/therapeutic use , Phytochemicals/therapeutic use , Protease Inhibitors/therapeutic use , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus/drug effects , Flavonoids/chemistry , Flavonoids/pharmacology , Humans , Immunologic Factors/chemistry , Immunologic Factors/pharmacology , Phytochemicals/chemistry , Phytochemicals/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology
11.
Eur J Med Chem ; 225: 113789, 2021 Dec 05.
Article in English | MEDLINE | ID: covidwho-1364001

ABSTRACT

SARS-CoV-2 as a positive-sense single-stranded RNA coronavirus caused the global outbreak of COVID-19. The main protease (Mpro) of the virus as the major enzyme processing viral polyproteins contributed to the replication and transcription of SARS-CoV-2 in host cells, and has been characterized as an attractive target in drug discovery. Herein, a set of 1,4-naphthoquinones with juglone skeleton were prepared and evaluated for the inhibitory efficacy against SARS-CoV-2 Mpro. More than half of the tested naphthoquinones could effectively inhibit the target enzyme with an inhibition rate of more than 90% at the concentration of 10 µM. In the structure-activity relationships (SARs) analysis, the characteristics of substituents and their position on juglone core scaffold were recognized as key ingredients for enzyme inhibitory activity. The most active compound, 2-acetyl-8-methoxy-1,4-naphthoquinone (15), which exhibited much higher potency in enzyme inhibitions than shikonin as the positive control, displayed an IC50 value of 72.07 ± 4.84 nM towards Mpro-mediated hydrolysis of the fluorescently labeled peptide. It fit well into the active site cavity of the enzyme by forming hydrogen bonds with adjacent amino acid residues in molecular docking studies. The results from in vitro antiviral activity evaluation demonstrated that the most potent Mpro inhibitor could significantly suppress the replication of SARS-CoV-2 in Vero E6 cells within the low micromolar concentrations, with its EC50 value of about 4.55 µM. It was non-toxic towards the host Vero E6 cells under tested concentrations. The present research work implied that juglone skeleton could be a primary template for the development of potent Mpro inhibitors.


Subject(s)
COVID-19/drug therapy , Naphthoquinones/chemistry , Protease Inhibitors/therapeutic use , SARS-CoV-2/enzymology , Viral Matrix Proteins/antagonists & inhibitors , Animals , Binding Sites , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Cell Survival/drug effects , Chlorocebus aethiops , Drug Design , Drug Evaluation, Preclinical , Humans , Hydrogen Bonding , Molecular Docking Simulation , Naphthoquinones/metabolism , Naphthoquinones/pharmacology , Naphthoquinones/therapeutic use , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , SARS-CoV-2/isolation & purification , Structure-Activity Relationship , Vero Cells , Viral Matrix Proteins/metabolism
12.
Antimicrob Agents Chemother ; 65(9): e0268020, 2021 08 17.
Article in English | MEDLINE | ID: covidwho-1360543

ABSTRACT

Antivirals targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could improve treatment of COVID-19. We evaluated the efficacy of clinically relevant hepatitis C virus (HCV) NS3 protease inhibitors (PIs) against SARS-CoV-2 and their interactions with remdesivir, the only direct-acting antiviral approved for COVID-19 treatment. HCV PIs showed differential potency in short-term treatment assays based on the detection of SARS-CoV-2 spike protein in Vero E6 cells. Linear PIs boceprevir, telaprevir, and narlaprevir had 50% effective concentrations (EC50) of ∼40 µM. Among the macrocyclic PIs, simeprevir had the highest (EC50, 15 µM) and glecaprevir the lowest (EC50, >178 µM) potency, with paritaprevir, grazoprevir, voxilaprevir, vaniprevir, danoprevir, and deldeprevir in between. Acyclic PIs asunaprevir and faldaprevir had EC50s of 72 and 23 µM, respectively. ACH-806, inhibiting the HCV NS4A protease cofactor, had an EC50 of 46 µM. Similar and slightly increased PI potencies were found in human hepatoma Huh7.5 cells and human lung carcinoma A549-hACE2 cells, respectively. Selectivity indexes based on antiviral and cell viability assays were highest for linear PIs. In short-term treatments, combination of macrocyclic but not linear PIs with remdesivir showed synergism in Vero E6 and A549-hACE2 cells. Longer-term treatment of infected Vero E6 and A549-hACE2 cells with 1-fold EC50 PI revealed minor differences in the barrier to SARS-CoV-2 escape. Viral suppression was achieved with 3- to 8-fold EC50 boceprevir or 1-fold EC50 simeprevir or grazoprevir, but not boceprevir, in combination with 0.4- to 0.8-fold EC50 remdesivir; these concentrations did not lead to viral suppression in single treatments. This study could inform the development and application of protease inhibitors for optimized antiviral treatments of COVID-19.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Hepatitis C , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Chlorocebus aethiops , Hepacivirus , Hepatitis C/drug therapy , Humans , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vero Cells , Viral Protease Inhibitors
13.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1348051

ABSTRACT

The identification of protein-ligand interaction plays a key role in biochemical research and drug discovery. Although deep learning has recently shown great promise in discovering new drugs, there remains a gap between deep learning-based and experimental approaches. Here, we propose a novel framework, named AIMEE, integrating AI model and enzymological experiments, to identify inhibitors against 3CL protease of SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2), which has taken a significant toll on people across the globe. From a bioactive chemical library, we have conducted two rounds of experiments and identified six novel inhibitors with a hit rate of 29.41%, and four of them showed an IC50 value <3 µM. Moreover, we explored the interpretability of the central model in AIMEE, mapping the deep learning extracted features to the domain knowledge of chemical properties. Based on this knowledge, a commercially available compound was selected and was proven to be an activity-based probe of 3CLpro. This work highlights the great potential of combining deep learning models and biochemical experiments for intelligent iteration and for expanding the boundaries of drug discovery. The code and data are available at https://github.com/SIAT-code/AIMEE.


Subject(s)
COVID-19/drug therapy , Protease Inhibitors/chemistry , SARS-CoV-2/chemistry , Small Molecule Libraries/chemistry , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Artificial Intelligence , COVID-19/genetics , COVID-19/virology , Drug Discovery , Humans , Ligands , Protease Inhibitors/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Small Molecule Libraries/therapeutic use
14.
Interdiscip Sci ; 13(3): 521-534, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1330422

ABSTRACT

The prolific spread of COVID-19 caused by a novel coronavirus (SARS-CoV-2) from its epicenter in Wuhan, China, to every nook and cranny of the world after December 2019, jeopardize the prevailing health system in the world and has raised serious concerns about human safety. Multi-directional efforts are made to design small molecule inhibitors, and vaccines and many other therapeutic options are practiced, but their final therapeutic potential is still to be tested. Using the old drug or vaccine or peptides could aid this process to avoid such long experimental procedures. Hence, here, we have repurposed a small peptide (ATLQAIAS) from the previous study, which reported the inhibitory effects of this peptide. We used in silico mutagenesis approach to design more peptides from the native wild peptide, which revealed that substitutions (T2W, T2Y, L3R, and A5W) could increase the binding affinity of the peptide towards the 3CLpro. Furthermore, using MD simulation and free energy calculation confirmed its dynamics stability and stronger binding affinities. Per-residue energy decomposition analysis revealed that the specified substitution significantly increased the binding affinity at the residue level. Our wide-ranging analyses of binding affinities disclosed that our designed peptide owns the potential to hinder the SARS-CoV-2 and will reduce the progression of SARS-CoV-2-borne pneumonia. Our research strongly suggests the experimental and clinical validation of these peptides to curtail the recent corona outbreak.


Subject(s)
Computer Simulation , Coronavirus 3C Proteases/antagonists & inhibitors , Molecular Dynamics Simulation , Mutagenesis , Peptides/chemistry , Peptides/pharmacology , SARS Virus , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Humans , Molecular Docking Simulation , Peptides/genetics , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , SARS Virus/chemistry , SARS Virus/genetics , SARS-CoV-2/enzymology , Thermodynamics
15.
Proc Natl Acad Sci U S A ; 118(29)2021 07 20.
Article in English | MEDLINE | ID: covidwho-1294550

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small-molecule 3CLpro inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme- and the cell-based assays. The K18-hACE2 mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and were proposed as a model for efficacy testing of antiviral agents. We treated lethally infected mice with a deuterated derivative of GC376. Treatment of K18-hACE2 mice at 24 h postinfection with a derivative (compound 2) resulted in increased survival of mice compared to vehicle-treated mice. Lung virus titers were decreased, and histopathological changes were ameliorated in compound 2-treated mice compared to vehicle-treated mice. Structural investigation using high-resolution crystallography illuminated binding interactions of 3CLpro of SARS-CoV-2 and SARS-CoV with deuterated variants of GC376. Taken together, deuterated GC376 variants have excellent potential as antiviral agents against SARS-CoV-2.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Protease Inhibitors/therapeutic use , Pyrrolidines/therapeutic use , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/genetics , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/pathology , Coronavirus 3C Proteases/chemistry , Coronavirus Papain-Like Proteases/chemistry , Crystallography, X-Ray , Deuterium , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Lung/pathology , Mice , Mice, Transgenic , Models, Molecular , Molecular Structure , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protein Conformation , Pyrrolidines/chemistry , SARS-CoV-2/enzymology , Sulfonic Acids , Transgenes
16.
SLAS Discov ; 26(9): 1189-1199, 2021 10.
Article in English | MEDLINE | ID: covidwho-1277903

ABSTRACT

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has a huge impact on the world. Although several vaccines have recently reached the market, the development of specific antiviral drugs against SARS-CoV-2 is an important additional strategy in fighting the pandemic. One of the most promising pharmacological targets is the viral main protease (Mpro). Here, we present an optimized biochemical assay procedure for SARS-CoV-2 Mpro. We have comprehensively investigated the influence of different buffer components and conditions on the assay performance and characterized Förster resonance energy transfer (FRET) substrates with a preference for 2-Abz/Tyr(3-NO2) FRET pairs. The substrates 2-AbzSAVLQSGTyr(3-NO2)R-OH, a truncated version of the established DABCYL/EDANS FRET substrate, and 2-AbzVVTLQSGTyr(3-NO2)R-OH are promising candidates for screening and inhibitor characterization. In the latter substrate, the incorporation of Val at position P5 improved the catalytic efficiency. Based on the obtained results, we present here a reproducible, reliable assay protocol using highly affordable buffer components.


Subject(s)
COVID-19/drug therapy , Drug Discovery , Peptide Hydrolases/genetics , Protease Inhibitors/isolation & purification , Antiviral Agents/isolation & purification , Antiviral Agents/therapeutic use , Biological Assay , COVID-19/epidemiology , COVID-19/virology , Cysteine Endopeptidases , Fluorescence Resonance Energy Transfer , Humans , Molecular Docking Simulation , Pandemics , Peptide Hydrolases/drug effects , Protease Inhibitors/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity
17.
J Infect Dis ; 224(Supplement_1): S1-S21, 2021 Jul 15.
Article in English | MEDLINE | ID: covidwho-1263668

ABSTRACT

The NIH Virtual SARS-CoV-2 Antiviral Summit, held on 6 November 2020, was organized to provide an overview on the status and challenges in developing antiviral therapeutics for coronavirus disease 2019 (COVID-19), including combinations of antivirals. Scientific experts from the public and private sectors convened virtually during a live videocast to discuss severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets for drug discovery as well as the preclinical tools needed to develop and evaluate effective small-molecule antivirals. The goals of the Summit were to review the current state of the science, identify unmet research needs, share insights and lessons learned from treating other infectious diseases, identify opportunities for public-private partnerships, and assist the research community in designing and developing antiviral therapeutics. This report includes an overview of therapeutic approaches, individual panel summaries, and a summary of the discussions and perspectives on the challenges ahead for antiviral development.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , COVID-19/virology , Drug Development , Humans , National Institutes of Health (U.S.) , Peptide Hydrolases/metabolism , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , United States , Virus Replication/drug effects
18.
Science ; 371(6536): 1374-1378, 2021 03 26.
Article in English | MEDLINE | ID: covidwho-1255508

ABSTRACT

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , COVID-19/pathology , COVID-19/virology , Cell Line , Cell Survival/drug effects , Chemokine CXCL10/metabolism , Disease Models, Animal , Drug Design , Humans , Interferon-beta/metabolism , Lung/immunology , Lung/pathology , Lung/virology , Mice , Mice, Transgenic , Oligopeptides , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Protease Inhibitors/therapeutic use , Protease Inhibitors/toxicity , Rats , Rats, Sprague-Dawley , Viral Load/drug effects , Virus Replication
19.
Biomed Pharmacother ; 140: 111742, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1233369

ABSTRACT

Here, drug repurposing and molecular docking were employed to screen approved MPP inhibitors and their derivatives to suggest a specific therapeutic agent for the treatment of COVID-19. The approved MPP inhibitors against HIV and HCV were prioritized, while RNA dependent RNA Polymerase (RdRp) inhibitor remdesivir including Favipiravir, alpha-ketoamide were studied as control groups. The target drug surface hotspot was also investigated through the molecular docking technique. Molecular dynamics was performed to determine the binding stability of docked complexes. Absorption, distribution, metabolism, and excretion analysis was conducted to understand the pharmacokinetics and drug-likeness of the screened MPP inhibitors. The results of the study revealed that Paritaprevir (-10.9 kcal/mol) and its analog (CID 131982844) (-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitors compared in this study, including remdesivir, Favipiravir, and alpha-ketoamide. A comparative study among the screened putative MPP inhibitors revealed that the amino acids T25, T26, H41, M49, L141, N142, G143, C145, H164, M165, E166, D187, R188, and Q189 are at potentially critical positions for being surface hotspots in the MPP of SARS-CoV-2. The top 5 predicted drugs (Paritaprevir, Glecaprevir, Nelfinavir, and Lopinavir) and the topmost analog showed conformational stability in the active site of the SARS-CoV-2 MP protein. The study also suggested that Paritaprevir and its analog (CID 131982844) might be effective against SARS-CoV-2. The current findings are limited to in silico analysis and lack in vivo efficacy testing; thus, we strongly recommend a quick assessment of Paritaprevir and its analog (CID 131982844) in a clinical trial.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Protease Inhibitors/therapeutic use , Drug Repositioning/methods , Humans , Molecular Docking Simulation/methods , Molecular Dynamics Simulation
20.
J Med Virol ; 93(5): 2722-2734, 2021 05.
Article in English | MEDLINE | ID: covidwho-1196526

ABSTRACT

The 21st century has witnessed three outbreaks of coronavirus (CoVs) infections caused by severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2. Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, spreads rapidly and since the discovery of the first COVID-19 infection in December 2019, has caused 1.2 million deaths worldwide and 226,777 deaths in the United States alone. The high amino acid similarity between SARS-CoV and SARS-CoV-2 viral proteins supports testing therapeutic molecules that were designed to treat SARS infections during the 2003 epidemic. In this review, we provide information on possible COVID-19 treatment strategies that act via inhibition of the two essential proteins of the virus, 3C-like protease (3CLpro ) or papain-like protease (PLpro ).


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Viral Proteases/drug effects , COVID-19/epidemiology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/drug effects , Coronavirus 3C Proteases/genetics , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/drug effects , Coronavirus Papain-Like Proteases/genetics , Humans , Middle East Respiratory Syndrome Coronavirus , Protease Inhibitors/therapeutic use , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics
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