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1.
J Mol Model ; 27(11): 341, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34731296

RESUMO

From the beginning of pandemic, more than 240 million people have been infected with a death rate higher than 2%. Indeed, the current exit strategy involving the spreading of vaccines must be combined with progress in effective treatment development. This scenario is sadly supported by the vaccine's immune activation time and the inequalities in the global immunization schedule. Bringing the crises under control means providing the world population with accessible and impactful new therapeutics. We screened a natural product library that contains a unique collection of 2370 natural products into the binding site of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). According to the docking score and to the interaction at the active site, three phenylethanoid glycosides (forsythiaside A, isoacteoside, and verbascoside) were selected. In order to provide better insight into the atomistic interaction and test the impact of the three selected compounds at the binding site, we resorted to a half microsecond-long molecular dynamics simulation. As a result, we are showing that forsythiaside A is the most stable molecule and it is likely to possess the highest inhibitory effect against SARS-CoV-2 Mpro. Phenylethanoid glycosides also have been reported to have both protease and kinase activity. This kinase inhibitory activity is very beneficial in fighting viruses inside the body as kinases are required for viral entry, metabolism, and/or reproduction. The dual activity (kinase/protease) of phenylethanoid glycosides makes them very promising anit-COVID-19 agents.


Assuntos
Antivirais/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/farmacologia , Glicosídeos/farmacologia , Antivirais/química , Sítios de Ligação , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Inibidores de Protease de Coronavírus/química , Avaliação Pré-Clínica de Medicamentos , Glucosídeos/química , Glucosídeos/metabolismo , Glucosídeos/farmacologia , Glicosídeos/química , Glicosídeos/metabolismo , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fenóis/química , Fenóis/metabolismo , Fenóis/farmacologia
3.
Nat Commun ; 12(1): 6055, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663813

RESUMO

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.


Assuntos
COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/administração & dosagem , Indóis/administração & dosagem , Leucina/administração & dosagem , Pirrolidinonas/administração & dosagem , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacocinética , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/análogos & derivados , Alanina/farmacocinética , Animais , COVID-19/virologia , Chlorocebus aethiops , Coronavirus Humano 229E/efeitos dos fármacos , Coronavirus Humano 229E/enzimologia , Inibidores de Protease de Coronavírus/efeitos adversos , Inibidores de Protease de Coronavírus/farmacocinética , Modelos Animais de Doenças , Desenho de Fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Células HeLa , Humanos , Indóis/efeitos adversos , Indóis/farmacocinética , Infusões Intravenosas , Leucina/efeitos adversos , Leucina/farmacocinética , Camundongos , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/enzimologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Células Vero
4.
Molecules ; 26(17)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34500664

RESUMO

This study aims to identify and isolate the secondary metabolites of Zingiber officinale using GC-MS, preparative TLC, and LC-MS/MS methods, to evaluate the inhibitory potency on SARS-CoV-2 3 chymotrypsin-like protease enzyme, as well as to study the molecular interaction and stability by using docking and molecular dynamics simulations. GC-MS analysis suggested for the isolation of terpenoids compounds as major compounds on methanol extract of pseudostems and rhizomes. Isolation and LC-MS/MS analysis identified 5-hydro-7, 8, 2'-trimethoxyflavanone (9), (E)-hexadecyl-ferulate (1), isocyperol (2), N-isobutyl-(2E,4E)-octadecadienamide (3), and nootkatone (4) from the rhizome extract, as well as from the leaves extract with the absence of 9. Three known steroid compounds, i.e., spinasterone (7), spinasterol (8), and 24-methylcholesta-7-en-3ß-on (6), were further identified from the pseudostem extract. Molecular docking showed that steroids compounds 7, 8, and 6 have lower predictive binding energies (MMGBSA) than other metabolites with binding energy of -87.91, -78.11, and -68.80 kcal/mole, respectively. Further characterization on the single isolated compound by NMR showed that 6 was identified and possessed 75% inhibitory activity on SARS-CoV-2 3CL protease enzyme that was slightly different with the positive control GC376 (77%). MD simulations showed the complex stability with compound 6 during 100 ns simulation time.


Assuntos
COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/farmacologia , Gengibre/química , Extratos Vegetais/farmacologia , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/ultraestrutura , Inibidores de Protease de Coronavírus/química , Inibidores de Protease de Coronavírus/isolamento & purificação , Inibidores de Protease de Coronavírus/uso terapêutico , Cristalografia por Raios X , Ensaios Enzimáticos , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Pirrolidinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Relação Estrutura-Atividade , Ácidos Sulfônicos/farmacologia
5.
Sci Rep ; 11(1): 17748, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493768

RESUMO

Based on WHO reports the new SARS-CoV-2 coronavirus is currently widespread all over the world. So far > 162 million cases have been confirmed, including > 3 million deaths. Because of the pandemic still spreading across the globe the accomplishment of computational methods to find new potential mechanisms of virus inhibitions is necessary. According to the fact that C60 fullerene (a sphere-shaped molecule consisting of carbon) has shown inhibitory activity against various protein targets, here the analysis of the potential binding mechanism between SARS-CoV-2 proteins 3CLpro and RdRp with C60 fullerene was done; it has resulted in one and two possible binding mechanisms, respectively. In the case of 3CLpro, C60 fullerene interacts in the catalytic binding pocket. And for RdRp in the first model C60 fullerene blocks RNA synthesis pore and in the second one it prevents binding with Nsp8 co-factor (without this complex formation, RdRp can't perform its initial functions). Then the molecular dynamics simulation confirmed the stability of created complexes. The obtained results might be a basis for other computational studies of 3CLPro and RdRp potential inhibition ways as well as the potential usage of C60 fullerene in the fight against COVID-19 disease.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Fulerenos/farmacologia , Antivirais/uso terapêutico , COVID-19/epidemiologia , COVID-19/virologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/ultraestrutura , Inibidores de Protease de Coronavírus/química , Inibidores de Protease de Coronavírus/farmacologia , Inibidores de Protease de Coronavírus/uso terapêutico , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , RNA-Polimerase RNA-Dependente de Coronavírus/ultraestrutura , Cristalografia por Raios X , Fulerenos/química , Fulerenos/uso terapêutico , Humanos , Simulação de Dinâmica Molecular , Inibidores da Síntese de Ácido Nucleico/química , Inibidores da Síntese de Ácido Nucleico/farmacologia , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Pandemias/prevenção & controle , RNA Viral/biossíntese , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , SARS-CoV-2/ultraestrutura
6.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502033

RESUMO

The novel coronavirus disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), rapidly spreading around the world, poses a major threat to the global public health. Herein, we demonstrated the binding mechanism of PF-07321332, α-ketoamide, lopinavir, and ritonavir to the coronavirus 3-chymotrypsin-like-protease (3CLpro) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CLpro with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CLpro-PF-07321332 and 3CLpro-α-ketoamide complexes remained stable compared with 3CLpro-ritonavir and 3CLpro-lopinavir. Investigating the dynamic behavior of ligand-protein interaction, ligands PF-07321332 and α-ketoamide showed stronger bonding via making interactions with catalytic dyad residues His41-Cys145 of 3CLpro. Lopinavir and ritonavir were unable to disrupt the catalytic dyad, as illustrated by increased bond length during the MD simulation. To decipher the ligand binding mode and affinity, ligand interactions with SARS-CoV-2 proteases and binding energy were calculated. The binding energy of the bespoke antiviral PF-07321332 clinical candidate was two times higher than that of α-ketoamide and three times than that of lopinavir and ritonavir. Our study elucidated in detail the binding mechanism of the potent PF-07321332 to 3CLpro along with the low potency of lopinavir and ritonavir due to weak binding affinity demonstrated by the binding energy data. This study will be helpful for the development and optimization of more specific compounds to combat coronavirus disease.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/farmacologia , Lactamas/farmacologia , Leucina/farmacologia , Nitrilas/farmacologia , Prolina/farmacologia , Antivirais/uso terapêutico , Domínio Catalítico/efeitos dos fármacos , Proteases 3C de Coronavírus/metabolismo , Inibidores de Protease de Coronavírus/uso terapêutico , Humanos , Lactamas/uso terapêutico , Leucina/uso terapêutico , Lopinavir/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nitrilas/uso terapêutico , Prolina/uso terapêutico , Ritonavir/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia
7.
Molecules ; 26(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34500548

RESUMO

The emergence of COVID-19 continues to pose severe threats to global public health. The pandemic has infected over 171 million people and claimed more than 3.5 million lives to date. We investigated the binding potential of antiviral cyanobacterial proteins including cyanovirin-N, scytovirin and phycocyanin with fundamental proteins involved in attachment and replication of SARS-CoV-2. Cyanovirin-N displayed the highest binding energy scores (-16.8 ± 0.02 kcal/mol, -12.3 ± 0.03 kcal/mol and -13.4 ± 0.02 kcal/mol, respectively) with the spike protein, the main protease (Mpro) and the papainlike protease (PLpro) of SARS-CoV-2. Cyanovirin-N was observed to interact with the crucial residues involved in the attachment of the human ACE2 receptor. Analysis of the binding affinities calculated employing the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) approach revealed that all forms of energy, except the polar solvation energy, favourably contributed to the interactions of cyanovirin-N with the viral proteins. With particular emphasis on cyanovirin-N, the current work presents evidence for the potential inhibition of SARS-CoV-2 by cyanobacterial proteins, and offers the opportunity for in vitro and in vivo experiments to deploy the cyanobacterial proteins as valuable therapeutics against COVID-19.


Assuntos
Antivirais/farmacologia , Proteínas de Bactérias/farmacologia , COVID-19/tratamento farmacológico , Inibidores de Protease de Coronavírus/farmacologia , Antivirais/uso terapêutico , Proteínas de Bactérias/uso terapêutico , Proteínas de Bactérias/ultraestrutura , COVID-19/virologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/ultraestrutura , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Proteases Semelhantes à Papaína de Coronavírus/ultraestrutura , Inibidores de Protease de Coronavírus/uso terapêutico , Inibidores de Protease de Coronavírus/ultraestrutura , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Mapeamento de Interação de Proteínas , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/ultraestrutura , Difração de Raios X
8.
Mar Drugs ; 19(7)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34356816

RESUMO

The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ΔGbinding < -33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ΔGbinding values of -43.8 and -34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.


Assuntos
Antozoários/química , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/farmacologia , Diterpenos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , COVID-19/virologia , Proteases 3C de Coronavírus/metabolismo , Inibidores de Protease de Coronavírus/química , Inibidores de Protease de Coronavírus/isolamento & purificação , Diterpenos/química , Diterpenos/isolamento & purificação , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , SARS-CoV-2/enzimologia , SARS-CoV-2/patogenicidade , Relação Estrutura-Atividade
9.
Int J Biol Macromol ; 188: 137-146, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34364941

RESUMO

COVID-19 is a disease caused by SARS-CoV-2, which has led to more than 4 million deaths worldwide. As a result, there is a worldwide effort to develop specific drugs for targeting COVID-19. Papain-like protease (PLpro) is an attractive drug target because it has multiple essential functions involved in processing viral proteins, including viral genome replication and removal of post-translational ubiquitination modifications. Here, we established two assays for screening PLpro inhibitors according to protease and anti-ISGylation activities, respectively. Application of the two screening techniques to the library of clinically approved drugs led to the discovery of tanshinone IIA sulfonate sodium and chloroxine with their IC50 values of lower than 10 µM. These two compounds were found to directly interact with PLpro and their molecular mechanisms of binding were illustrated by docking and molecular dynamics simulations. The results highlight the usefulness of the two developed screening techniques for locating PLpro inhibitors.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/farmacologia , Reposicionamento de Medicamentos , SARS-CoV-2/enzimologia , Antivirais/química , Sítios de Ligação , Cloroquinolinóis/química , Cloroquinolinóis/farmacologia , Proteases Semelhantes à Papaína de Coronavírus/genética , Proteases Semelhantes à Papaína de Coronavírus/isolamento & purificação , Inibidores de Protease de Coronavírus/química , Ensaios de Triagem em Larga Escala/métodos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fenantrenos/química , Fenantrenos/farmacologia , SARS-CoV-2/efeitos dos fármacos
10.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299333

RESUMO

In the last year, the COVID-19 pandemic has highly affected the lifestyle of the world population, encouraging the scientific community towards a great effort on studying the infection molecular mechanisms. Several vaccine formulations are nowadays available and helping to reach immunity. Nevertheless, there is a growing interest towards the development of novel anti-covid drugs. In this scenario, the main protease (Mpro) represents an appealing target, being the enzyme responsible for the cleavage of polypeptides during the viral genome transcription. With the aim of sharing new insights for the design of novel Mpro inhibitors, our research group developed a machine learning approach using the support vector machine (SVM) classification. Starting from a dataset of two million commercially available compounds, the model was able to classify two hundred novel chemo-types as potentially active against the viral protease. The compounds labelled as actives by SVM were next evaluated through consensus docking studies on two PDB structures and their binding mode was compared to well-known protease inhibitors. The best five compounds selected by consensus docking were then submitted to molecular dynamics to deepen binding interactions stability. Of note, the compounds selected via SVM retrieved all the most important interactions known in the literature.


Assuntos
COVID-19/tratamento farmacológico , Inibidores de Protease de Coronavírus/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , SARS-CoV-2/efeitos dos fármacos , Máquina de Vetores de Suporte , Antivirais/farmacologia , COVID-19/virologia , Inibidores de Protease de Coronavírus/metabolismo , Bases de Dados de Produtos Farmacêuticos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , SARS-CoV-2/enzimologia , Bibliotecas de Moléculas Pequenas , Aprendizado de Máquina Supervisionado , Proteínas não Estruturais Virais/metabolismo , Proteases Virais/metabolismo
11.
Fitoterapia ; 152: 104909, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33894315

RESUMO

3-Chymotrypsin-like protease (3CLpro) is a virally encoded main proteinase that is pivotal for the viral replication across a broad spectrum of coronaviruses. This study aims to discover the naturally occurring SARS-CoV-2 3CLpro inhibitors from herbal constituents, as well as to investigate the inhibitory mechanism of the newly identified efficacious SARS-CoV-2 3CLpro inhibitors. Following screening of the inhibitory potentials of eighty herbal products against SARS-CoV-2 3CLpro, Ginkgo biloba leaves extract (GBLE) was found with the most potent SARS-CoV-2 3CLpro inhibition activity (IC50 = 6.68 µg/mL). Inhibition assays demonstrated that the ginkgolic acids (GAs) and the bioflavones isolated from GBLE displayed relatively strong SARS-CoV-2 3CLpro inhibition activities (IC50 < 10 µM). Among all tested constituents, GA C15:0, GA C17:1 and sciadopitysin displayed potent 3CLpro inhibition activities, with IC50 values of less than 2 µM. Further inhibition kinetic studies and docking simulations clearly demonstrated that two GAs and sciadopitysin strongly inhibit SARS-CoV-2 3CLprovia a reversible and mixed inhibition manner. Collectively, this study found that both GBLE and the major constituents in this herbal product exhibit strong SARS-CoV-2 3CLpro inhibition activities, which offer several promising leading compounds for developing novel anti-COVID-19 medications via targeting on 3CLpro.


Assuntos
Antivirais/farmacologia , COVID-19 , Inibidores de Protease de Coronavírus/farmacologia , Ginkgo biloba/química , Extratos Vegetais/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Antivirais/uso terapêutico , Biflavonoides/farmacologia , Biflavonoides/uso terapêutico , COVID-19/tratamento farmacológico , Inibidores de Protease de Coronavírus/uso terapêutico , Flavonas/farmacologia , Flavonas/uso terapêutico , Humanos , Estrutura Molecular , Fitoterapia , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , SARS-CoV-2/enzimologia , Salicilatos/farmacologia , Salicilatos/uso terapêutico
12.
Chem Soc Rev ; 50(6): 3647-3655, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33524090

RESUMO

Clinically approved antiviral drugs are currently available for only 10 of the more than 220 viruses known to infect humans. The SARS-CoV-2 outbreak has exposed the critical need for compounds that can be rapidly mobilised for the treatment of re-emerging or emerging viral diseases, while vaccine development is underway. We review the current status of antiviral therapies focusing on RNA viruses, highlighting strategies for antiviral drug discovery and discuss the challenges, solutions and options to accelerate drug discovery efforts.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Descoberta de Drogas/métodos , Terapia de Alvo Molecular/métodos , Pandemias/prevenção & controle , RNA Viral/antagonistas & inibidores , Antivirais/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , COVID-19/prevenção & controle , COVID-19/virologia , Inibidores de Protease de Coronavírus/química , Inibidores de Protease de Coronavírus/farmacologia , Humanos , Simulação de Acoplamento Molecular , Inibidores da Síntese de Ácido Nucleico/química , Inibidores da Síntese de Ácido Nucleico/farmacologia , RNA Viral/química , RNA Viral/genética , RNA Viral/metabolismo , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , SARS-CoV-2/genética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
13.
Nat Commun ; 12(1): 668, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510133

RESUMO

Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 µM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.


Assuntos
COVID-19/tratamento farmacológico , Inibidores de Protease de Coronavírus/farmacologia , SARS-CoV-2/efeitos dos fármacos , Proteases Virais/efeitos dos fármacos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Antivirais/farmacologia , Linhagem Celular , Chlorocebus aethiops , Humanos , Indóis/farmacologia , Piridinas/farmacologia , Células Vero , Proteases Virais/metabolismo
14.
Hum Vaccin Immunother ; 17(4): 1113-1121, 2021 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-33064630

RESUMO

A novel coronavirus (2019-nCov) emerged in China, at the end of December 2019 which posed an International Public Health Emergency, and later declared as a global pandemic by the World Health Organization (WHO). The International Committee on Taxonomy of Viruses (ICTV) named it SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2), while the disease was named COVID-19 (Coronavirus Disease- 2019). Many questions related to the exact mode of transmission, animal origins, and antiviral therapeutics are not clear yet. Nevertheless, it is required to urgently launch a new protocol to evaluate the side effects of unapproved vaccines and antiviral therapeutics to accelerate the clinical application of new drugs. In this review, we highlight the most salient characteristics and recent findings of COVID-19 disease, molecular virology, interspecies mechanisms, and health consequences related to this disease.


Assuntos
Antivirais/farmacologia , Vacinas contra COVID-19/imunologia , COVID-19/patologia , COVID-19/transmissão , Inibidores de Protease de Coronavírus/farmacologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Antivirais/efeitos adversos , COVID-19/tratamento farmacológico , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Quirópteros/virologia , Humanos , Lopinavir/farmacologia , Ritonavir/farmacologia , SARS-CoV-2/efeitos dos fármacos , Ligação Viral , Internalização do Vírus
15.
Curr Drug Discov Technol ; 18(5): e17092020186048, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32957889

RESUMO

BACKGROUND: The recent outbreak of Coronavirus SARS-CoV-2 (Covid-19), which has rapidly spread around the world in about three months with tens of thousands of deaths recorded so far is a global concern. An urgent need for potential therapeutic intervention is of necessity. Mpro is an attractive druggable target for the development of anti-COVID-19 drug development. METHODS: Compounds previously characterized by Melissa officinalis were queried against the main protease of coronavirus SARS-CoV-2 using a computational approach. RESULTS: Melitric acid A and salvanolic acid A had higher affinity than lopinavir and ivermectin using both AutodockVina and XP docking algorithms. The computational approach was employed in the generation of the QSAR model using automated QSAR, and in the docking of ligands from Melissa officinalis with SARS-CoV-2 Mpro inhibitors. The best model obtained was KPLS_Radial_ 28 (R2 = 0.8548 and Q2=0.6474, which was used in predicting the bioactivity of the lead compounds. Molecular mechanics based MM-GBSA confirmed salvanolic acid A as the compound with the highest free energy and predicted bioactivity of 4.777; it interacted with His-41 of the catalytic dyad (Cys145-His41) of SARS-CoV-2 main protease (Mpro), as this may hinder the cutting of inactive viral protein into active ones capable of replication. CONCLUSION: Salvanolic acid A can be further evaluated as a potential Mpro inhibitor.


Assuntos
COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/farmacologia , Melissa/química , SARS-CoV-2 , Antivirais/farmacologia , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Plantas Medicinais , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia
16.
Biochem Biophys Res Commun ; 538: 72-79, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33276953

RESUMO

SARS-CoV-2 papain-like protease is considered as an important potential target for anti-SARS-CoV-2 drug discovery due to its crucial roles in viral spread and innate immunity. Here, we have utilized an in silico molecular docking approach to identify the possible inhibitors of the SARS-CoV-2 papain-like protease, by screening 21 antiviral, antifungal and anticancer compounds. Among them, Neobavaisoflavone has the highest binding energy for SARS-CoV-2 papain-like protease. These molecules could bind near the SARS-CoV-2 papain-like protease crucial catalytic triad, ubiquitination and ISGylation residues: Trp106, Asn109, Cys111, Met208, Lys232, Pro247, Tyr268, Gln269, His272, Asp286 and Thr301. Because blocking the papain-like protease is an important strategy in fighting against viruses, these compounds might be promising candidates for therapeutic intervention against COVID-19.


Assuntos
Proteases Semelhantes à Papaína de Coronavírus/química , Inibidores de Protease de Coronavírus/química , Inibidores de Cisteína Proteinase/química , Descoberta de Drogas/métodos , Isoflavonas/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Humanos , Isoflavonas/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica
17.
Biochem Biophys Res Commun ; 538: 63-71, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33288200

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an unprecedented global health crisis. It is particularly urgent to develop clinically effective therapies to contain the pandemic. The main protease (Mpro) and the RNA-dependent RNA polymerase (RdRP), which are responsible for the viral polyprotein proteolytic process and viral genome replication and transcription, respectively, are two attractive drug targets for SARS-CoV-2. This review summarizes up-to-date progress in the structural and pharmacological aspects of those two key targets above. Different classes of inhibitors individually targeting Mpro and RdRP are discussed, which could promote drug development to treat SARS-CoV-2 infection.


Assuntos
Antivirais/química , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Inibidores de Protease de Coronavírus/química , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , RNA-Polimerase RNA-Dependente de Coronavírus/química , Inibidores Enzimáticos/química , SARS-CoV-2/enzimologia , Antivirais/farmacologia , Inibidores de Protease de Coronavírus/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Conformação Proteica , SARS-CoV-2/efeitos dos fármacos
18.
J Antimicrob Chemother ; 76(2): 396-412, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33254234

RESUMO

OBJECTIVES: To define key genetic elements, single or in clusters, underlying SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) evolutionary diversification across continents, and their impact on drug-binding affinity and viral antigenicity. METHODS: A total of 12 150 SARS-CoV-2 sequences (publicly available) from 69 countries were analysed. Mutational clusters were assessed by hierarchical clustering. Structure-based virtual screening (SBVS) was used to select the best inhibitors of 3-chymotrypsin-like protease (3CL-Pr) and RNA-dependent RNA polymerase (RdRp) among the FDA-approved drugs and to evaluate the impact of mutations on binding affinity of these drugs. The impact of mutations on epitope recognition was predicted following Grifoni et al. (Cell Host Microbe 2020. 27: 671-80.). RESULTS: Thirty-five key mutations were identified (prevalence: ≥0.5%), residing in different viral proteins. Sixteen out of 35 formed tight clusters involving multiple SARS-CoV-2 proteins, highlighting intergenic co-evolution. Some clusters (including D614GSpike + P323LRdRp + R203KN + G204RN) occurred in all continents, while others showed a geographically restricted circulation (T1198KPL-Pr + P13LN + A97VRdRp in Asia, L84SORF-8 + S197LN in Europe, Y541CHel + H504CHel + L84SORF-8 in America and Oceania). SBVS identified 20 best RdRp inhibitors and 21 best 3CL-Pr inhibitors belonging to different drug classes. Notably, mutations in RdRp or 3CL-Pr modulate, positively or negatively, the binding affinity of these drugs. Among them, P323LRdRp (prevalence: 61.9%) reduced the binding affinity of specific compounds including remdesivir while it increased the binding affinity of the purine analogues penciclovir and tenofovir, suggesting potential hypersusceptibility. Finally, specific mutations (including Y541CHel + H504CHel) strongly hampered recognition of Class I/II epitopes, while D614GSpike profoundly altered the structural stability of a recently identified B cell epitope target of neutralizing antibodies (amino acids 592-620). CONCLUSIONS: Key genetic elements reflect geographically dependent SARS-CoV-2 genetic adaptation, and may play a potential role in modulating drug susceptibility and hampering viral antigenicity. Thus, a close monitoring of SARS-CoV-2 mutational patterns is crucial to ensure the effectiveness of treatments and vaccines worldwide.


Assuntos
Adaptação Biológica/genética , Antivirais/metabolismo , COVID-19/imunologia , Proteases 3C de Coronavírus/genética , Inibidores de Protease de Coronavírus/metabolismo , RNA-Polimerase RNA-Dependente de Coronavírus/genética , SARS-CoV-2/genética , América , Sequência de Aminoácidos , Antígenos Virais/sangue , Antivirais/uso terapêutico , Ásia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Simulação por Computador , Proteases 3C de Coronavírus/metabolismo , Inibidores de Protease de Coronavírus/uso terapêutico , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Europa (Continente) , Evolução Molecular , Humanos , Simulação de Acoplamento Molecular , Família Multigênica , Mutação/genética , Taxa de Mutação , Oceania , Ligação Proteica , SARS-CoV-2/enzimologia , Topografia Médica
20.
Comput Biol Chem ; 89: 107408, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33137690

RESUMO

Caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the COVID-19 pandemic is ongoing, with no proven safe and effective vaccine to date. Further, effective therapeutic agents for COVID-19 are limited, and as a result, the identification of potential small molecule antiviral drugs is of particular importance. A critical antiviral target is the SARS-CoV-2 main protease (Mpro), and our aim was to identify lead compounds with potential inhibitory effects. We performed an initial molecular docking screen of 300 small molecules, which included phenolic compounds and fatty acids from our OliveNet™ library (224), and an additional group of curated pharmacological and dietary compounds. The prototypical α-ketoamide 13b inhibitor was used as a control to guide selection of the top 30 compounds with respect to binding affinity to the Mpro active site. Further studies and analyses including blind docking were performed to identify hypericin, cyanidin-3-O-glucoside and SRT2104 as potential leads. Molecular dynamics simulations demonstrated that hypericin (ΔG = -18.6 and -19.3 kcal/mol), cyanidin-3-O-glucoside (ΔG = -50.8 and -42.1 kcal/mol), and SRT2104 (ΔG = -8.7 and -20.6 kcal/mol), formed stable interactions with the Mpro active site. An enzyme-linked immunosorbent assay indicated that, albeit, not as potent as the covalent positive control (GC376), our leads inhibited the Mpro with activity in the micromolar range, and an order of effectiveness of hypericin and cyanidin-3-O-glucoside > SRT2104 > SRT1720. Overall, our findings, and those highlighted by others indicate that hypericin and cyanidin-3-O-glucoside are suitable candidates for progress to in vitro and in vivo antiviral studies.


Assuntos
Antivirais/farmacologia , Proteases 3C de Coronavírus/metabolismo , Inibidores de Protease de Coronavírus/farmacologia , Ensaio de Imunoadsorção Enzimática , SARS-CoV-2/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Antivirais/química , Inibidores de Protease de Coronavírus/química , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Modelos Moleculares , Fenóis/química , Fenóis/farmacologia , SARS-CoV-2/metabolismo , Bibliotecas de Moléculas Pequenas/química
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