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1.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204256

RESUMO

The marine carotenoids fucoxanthin and siphonaxanthin are powerful antioxidants that are attracting focused attention to identify a variety of health benefits and industry applications. In this study, the binding energy of these carotenoids with the SARS-CoV-2 Spike-glycoprotein was predicted by molecular docking simulation, and their inhibitory activity was confirmed with SARS-CoV-2 pseudovirus on HEK293 cells overexpressing angiotensin-converting enzyme 2 (ACE2). Siphonaxanthin from Codium fragile showed significant antiviral activity with an IC50 of 87.4 µM against SARS-CoV-2 pseudovirus entry, while fucoxanthin from Undaria pinnatifida sporophyll did not. The acute toxicities were predicted to be relatively low, and pharmacokinetic predictions indicate GI absorption. Although further studies are needed to elucidate the inhibition of viral infection by siphonaxanthin, these results provide useful information in the application of these marine carotenoids for the treatment and prevention of COVID-19.


Assuntos
Antivirais/farmacologia , SARS-CoV-2/fisiologia , Internalização do Vírus/efeitos dos fármacos , Xantofilas/química , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antivirais/química , Antivirais/uso terapêutico , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Sobrevivência Celular/efeitos dos fármacos , Clorófitas/química , Clorófitas/metabolismo , Células HEK293 , Meia-Vida , Humanos , Simulação de Acoplamento Molecular , Feófitas/química , Feófitas/metabolismo , Ratos , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Xantofilas/metabolismo , Xantofilas/farmacologia , Xantofilas/uso terapêutico
2.
Molecules ; 26(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208050

RESUMO

Potential effects of tea and its constituents on SARS-CoV-2 infection were assessed in vitro. Infectivity of SARS-CoV-2 was decreased to 1/100 to undetectable levels after a treatment with black tea, green tea, roasted green tea, or oolong tea for 1 min. An addition of (-) epigallocatechin gallate (EGCG) significantly inactivated SARS-CoV-2, while the same concentration of theasinensin A (TSA) and galloylated theaflavins including theaflavin 3,3'-di-O-gallate (TFDG) had more remarkable anti-viral activities. EGCG, TSA, and TFDG at 1 mM, 40 µM, and 60 µM, respectively, which are comparable to the concentrations of these compounds in tea beverages, significantly reduced infectivity of the virus, viral RNA replication in cells, and secondary virus production from the cells. EGCG, TSA, and TFDG significantly inhibited interaction between recombinant ACE2 and RBD of S protein. These results suggest potential usefulness of tea in prevention of person-to-person transmission of the novel coronavirus.


Assuntos
Antivirais/farmacologia , Biflavonoides/química , Catequina/química , Ácido Gálico/análogos & derivados , SARS-CoV-2/fisiologia , Chá/química , Replicação Viral/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antivirais/química , Biflavonoides/farmacologia , COVID-19/patologia , COVID-19/virologia , Catequina/análogos & derivados , Catequina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Ácido Gálico/química , Ácido Gálico/farmacologia , Humanos , Mapas de Interação de Proteínas/efeitos dos fármacos , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Chá/metabolismo , Células Vero
3.
Molecules ; 26(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202092

RESUMO

(1) Background: The COVID-19 pandemic lacks treatments; for this reason, the search for potential compounds against therapeutic targets is still necessary. Bioinformatics tools have allowed the rapid in silico screening of possible new metabolite candidates from natural resources or repurposing known ones. Thus, in this work, we aimed to select phytochemical candidates from Peruvian plants with antiviral potential against three therapeutical targets of SARS-CoV-2. (2) Methods: We applied in silico technics, such as virtual screening, molecular docking, molecular dynamics simulation, and MM/GBSA estimation. (3) Results: Rutin, a compound present in Peruvian native plants, showed affinity against three targets of SARS-CoV-2. The molecular dynamics simulation demonstrated the high stability of receptor-ligand systems during the time of the simulation. Our results showed that the Mpro-Rutin system exhibited higher binding free energy than PLpro-Rutin and N-Rutin systems through MM/GBSA analysis. (4) Conclusions: Our study provides insight on natural metabolites from Peruvian plants with therapeutical potential. We found Rutin as a potential candidate with multiple pharmacological properties against SARS-CoV-2.


Assuntos
Antivirais/química , Antivirais/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Plantas/química , Plantas/metabolismo , Asteraceae/química , Asteraceae/metabolismo , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Proteínas do Nucleocapsídeo de Coronavírus/antagonistas & inibidores , Proteínas do Nucleocapsídeo de Coronavírus/química , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Proteases Semelhantes à Papaína de Coronavírus/química , Bases de Dados Factuais , Humanos , Lepidium/química , Lepidium/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peru , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/química , Rutina/química , Rutina/farmacologia , SARS-CoV-2
4.
Molecules ; 26(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202374

RESUMO

A newly diagnosed coronavirus in 2019 (COVID-19) has affected all human activities since its discovery. Flavonoids commonly found in the human diet have attracted a lot of attention due to their remarkable biological activities. This paper provides a comprehensive review of the benefits of flavonoids in COVID-19 disease. Previously-reported effects of flavonoids on five RNA viruses with similar clinical manifestations and/or pharmacological treatments, including influenza, human immunodeficiency virus (HIV), severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and Ebola, were considered. Flavonoids act via direct antiviral properties, where they inhibit different stages of the virus infective cycle and indirect effects when they modulate host responses to viral infection and subsequent complications. Flavonoids have shown antiviral activity via inhibition of viral protease, RNA polymerase, and mRNA, virus replication, and infectivity. The compounds were also effective for the regulation of interferons, pro-inflammatory cytokines, and sub-cellular inflammatory pathways such as nuclear factor-κB and Jun N-terminal kinases. Baicalin, quercetin and its derivatives, hesperidin, and catechins are the most studied flavonoids in this regard. In conclusion, dietary flavonoids are promising treatment options against COVID-19 infection; however, future investigations are recommended to assess the antiviral properties of these compounds on this disease.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Flavonoides/farmacologia , Compostos Fitoquímicos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/uso terapêutico , Flavonoides/química , Flavonoides/uso terapêutico , Humanos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
5.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202844

RESUMO

The COVID-19 pandemic, as well as the more general global increase in viral diseases, has led researchers to look to the plant kingdom as a potential source for antiviral compounds. Since ancient times, herbal medicines have been extensively applied in the treatment and prevention of various infectious diseases in different traditional systems. The purpose of this review is to highlight the potential antiviral activity of plant compounds as effective and reliable agents against viral infections, especially by viruses from the coronavirus group. Various antiviral mechanisms shown by crude plant extracts and plant-derived bioactive compounds are discussed. The understanding of the action mechanisms of complex plant extract and isolated plant-derived compounds will help pave the way towards the combat of this life-threatening disease. Further, molecular docking studies, in silico analyses of extracted compounds, and future prospects are included. The in vitro production of antiviral chemical compounds from plants using molecular pharming is also considered. Notably, hairy root cultures represent a promising and sustainable way to obtain a range of biologically active compounds that may be applied in the development of novel antiviral agents.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Extratos Vegetais/farmacologia , Plantas Medicinais/química , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Antivirais/imunologia , Antivirais/uso terapêutico , Simulação por Computador , Humanos , Agricultura Molecular/métodos , Extratos Vegetais/química , Extratos Vegetais/imunologia , Extratos Vegetais/uso terapêutico , Plantas Medicinais/imunologia , SARS-CoV-2/fisiologia , Replicação Viral/efeitos dos fármacos
6.
Molecules ; 26(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205704

RESUMO

The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure-activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Anti-Inflamatórios não Esteroides/metabolismo , Antivirais/química , Antivirais/farmacologia , Auranofina/química , Auranofina/farmacologia , Sítios de Ligação , COVID-19/complicações , Biologia Computacional , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Bases de Dados de Compostos Químicos , Humanos , Indometacina/química , Indometacina/farmacologia , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ligação Proteica , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfimpirazona/química , Sulfimpirazona/farmacologia , Estados Unidos , United States Food and Drug Administration
7.
Molecules ; 26(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205768

RESUMO

Since December 2019, novel coronavirus disease 2019 (COVID-19) pandemic has caused tremendous economic loss and serious health problems worldwide. In this study, we investigated 14 natural compounds isolated from Amphimedon sp. via a molecular docking study, to examine their ability to act as anti-COVID-19 agents. Moreover, the pharmacokinetic properties of the most promising compounds were studied. The docking study showed that virtually screened compounds were effective against the new coronavirus via dual inhibition of SARS-CoV-2 RdRp and the 3CL main protease. In particular, nakinadine B (1), 20-hepacosenoic acid (11) and amphimedoside C (12) were the most promising compounds, as they demonstrated good interactions with the pockets of both enzymes. Based on the analysis of the molecular docking results, compounds 1 and 12 were selected for molecular dynamics simulation studies. Our results showed Amphimedon sp. to be a rich source for anti-COVID-19 metabolites.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Proteases 3C de Coronavírus/química , Poríferos/química , Poríferos/metabolismo , RNA Polimerase Dependente de RNA/química , SARS-CoV-2/efeitos dos fármacos , Amino Açúcares/química , Amino Açúcares/farmacologia , Animais , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacocinética , COVID-19/tratamento farmacológico , Biologia Computacional , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Humanos , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Piridinas/química , Piridinas/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/metabolismo , SARS-CoV-2/enzimologia , SARS-CoV-2/metabolismo
8.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206406

RESUMO

Spanish flu, polio epidemics, and the ongoing COVID-19 pandemic are the most profound examples of severe widespread diseases caused by RNA viruses. The coronavirus pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demands affordable and reliable assays for testing antivirals. To test inhibitors of viral proteases, we have developed an inexpensive high-throughput assay based on fluorescent energy transfer (FRET). We assayed an array of inhibitors for papain-like protease from SARS-CoV-2 and validated it on protease from the tick-borne encephalitis virus to emphasize its versatility. The reaction progress is monitored as loss of FRET signal of the substrate. This robust and reproducible assay can be used for testing the inhibitors in 96- or 384-well plates.


Assuntos
Antivirais/farmacologia , Transferência Ressonante de Energia de Fluorescência/métodos , Ensaios de Triagem em Larga Escala/métodos , Inibidores de Proteases/farmacologia , Vírus de RNA/enzimologia , COVID-19/tratamento farmacológico , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Proteases Semelhantes à Papaína de Coronavírus/química , Proteases Semelhantes à Papaína de Coronavírus/genética , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Avaliação Pré-Clínica de Medicamentos , Vírus da Encefalite Transmitidos por Carrapatos/enzimologia , Corantes Fluorescentes/química , Humanos , RNA Helicases/antagonistas & inibidores , RNA Helicases/química , RNA Helicases/genética , RNA Helicases/metabolismo , SARS-CoV-2/enzimologia , Serina Endopeptidases/química , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
9.
J Mol Model ; 27(8): 221, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34236507

RESUMO

Natural products have served human life as medications for centuries. During the outbreak of COVID-19, a number of naturally derived compounds and extracts have been tested or used as potential remedies against COVID-19. Tetradenia riparia extract is one of the plant extracts that have been deployed and claimed to manage and control COVID-19 by some communities in Tanzania and other African countries. The active compounds isolated from T. riparia are known to possess various biological properties including antimalarial and antiviral. However, the underlying mechanism of the active compounds against SARS-CoV-2 remains unknown. Results in the present work have been interpreted from the view point of computational methods including molecular dynamics, free energy methods, and metadynamics to establish the related mechanism of action. Among the constituents of T. riparia studied, luteolin inhibited viral cell entry and was thermodynamically stable. The title compound exhibit residence time and unbinding kinetics of 68.86 ms and 0.014 /ms, respectively. The findings suggest that luteolin could be potent blocker of SARS-CoV-2 cell entry. The study shades lights towards identification of bioactive constituents from T. riparia against COVID-19, and thus bioassay can be carried out to further validate such observations.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Luteolina/farmacologia , Simulação de Dinâmica Molecular , Extratos Vegetais/farmacologia , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/isolamento & purificação , Antivirais/metabolismo , Sítios de Ligação , COVID-19/virologia , Interações Hospedeiro-Patógeno , Humanos , Cinética , Lamiaceae/química , Luteolina/isolamento & purificação , Luteolina/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/metabolismo , Ligação Proteica , Conformação Proteica , Receptores Virais/metabolismo , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo
10.
J Mol Model ; 27(8): 222, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34236527

RESUMO

The crescent evolution of a global pandemic COVID-19 and its respiratory syndrome (SARS-Cov-2) has been a constant concern (Ghosh 2021; Khan et al. 2021; Alazmi and Motwalli 2020; Vargas et al. 2020). The absence of a proven and effective medication has compelled all the scientific community to search for a new drug. The use of known drugs is a faster way to develop new therapies. Molecular docking is a powerful tool (Gao et al. J Mol Model 10: 44-54, 2004; Singh et al. J Mol Model 18: 39-51, 2012; Schulz-Gasch and Stahl J Mol Model 9:47-57, 2003) to study the interaction of potential drugs with SARS-CoV-2, Alsalme et al. (2020) and Sanders et al. (2020) spike protein as a consequence the main goal of this article is to present the result of the study of an interaction between (R and S)-Linezolid with receptor-binding domain (RBD) of SARS-Cov-2 spike protein complexed with human Angiostensin-converting enzyme 2 (ACE2) (6vW1 - from PDB). The Linezolid enantiomers were optimized at B3LYP/6-311++G(2d,p) level of theory. Molecular docking of the system (S)-Linezolid⋯RBD⋯ACE2 and (R)-Linezolid⋯RBD⋯ACE2 was performed, the analysis was made using LigPlot+ and NCIplot software packages, to understand the intermolecular interactions. The UV-Vis and ECD of the complexes - (R and S)-Linezolid⋯RBD⋯ACE2 were performed in two layers with DFT/6-311++G(3df,2p) and DFT/6-31G(d), respectively. The results showed that only the (S)-Linezolid had a stable interaction with - 8.05 kcal.mol- 1, whereas all the R-enantiomeric configurations had positive values of binding energy. The (S)-Linezolid had the same interactions as in the (S)-Linezolid ⋯ Haluarcula morismortui Ribosomal system, where it is well-known the fact that the latter has biological activity. A specific interaction on the fluorine ring justified an attenuation on the ECD signal, in comparison to isolated species. Therefore, some biological activity of (S)-Linezolid with SARS-CoV-2 RBD was expected, indicated by the modification of its ECD signal and justified by a similar interaction in the S-Linezolid⋯Haluarcula marismortui Ribosomal system.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Linezolida/farmacologia , Simulação de Acoplamento Molecular , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/metabolismo , Sítios de Ligação , COVID-19/virologia , Interações Hospedeiro-Patógeno , Humanos , Cinética , Linezolida/metabolismo , Ligação Proteica , Conformação Proteica , Receptores Virais/metabolismo , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Relação Estrutura-Atividade
11.
Molecules ; 26(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200418

RESUMO

This paper reports the synthesis of branched alkylene guanidines using microfluidic technologies. We describe the preparation of guanidine derivatives at lower temperatures, and with significantly less time than that required in the previously applicable method. Furthermore, the use of microfluidics allows the attainment of high-purity products with a low residual monomer content, which can expand the range of applications of this class of compounds. For all the samples obtained, the molecular-weight characteristics are calculated, based on which the optimal condensation conditions are established. Additionally, in this work, the antiviral activity of the alkylene guanidine salt against the SARS-CoV-2 virus is confirmed.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Guanidinas/síntese química , Guanidinas/farmacologia , Microfluídica/métodos , SARS-CoV-2/efeitos dos fármacos , Animais , COVID-19 , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Chlorocebus aethiops , Concentração Inibidora 50 , Espectrometria de Massas por Ionização por Electrospray , Células Vero
12.
Viruses ; 13(6)2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200602

RESUMO

The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the world is still expanding. Thus, there is an urgent need to better understand this novel virus and find a way to control its spread. Like other coronaviruses, the nucleocapsid (N) protein is one of the most crucial structural components of SARS-CoV-2. This protein shares 90% homology with the severe acute respiratory syndrome coronavirus N protein, implying functional significance. Based on the evolutionary conservation of the N protein in coronavirus, we reviewed the currently available knowledge regarding the SARS-CoV-2 N protein in terms of structure, biological functions, and clinical application as a drug target or vaccine candidate.


Assuntos
Vacinas contra COVID-19/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , SARS-CoV-2/química , SARS-CoV-2/metabolismo , Animais , Antivirais/farmacologia , COVID-19/prevenção & controle , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Humanos , Camundongos , Preparações Farmacêuticas , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
13.
Biomolecules ; 11(6)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201172

RESUMO

The phytotherapeutic properties of Glycyrrhiza glabra (licorice) extract are mainly attributed to glycyrrhizin (GR) and glycyrrhetinic acid (GA). Among their possible pharmacological actions, the ability to act against viruses belonging to different families, including SARS coronavirus, is particularly important. With the COVID-19 emergency and the urgent need for compounds to counteract the pandemic, the antiviral properties of GR and GA, as pure substances or as components of licorice extract, attracted attention in the last year and supported the launch of two clinical trials. In silico docking studies reported that GR and GA may directly interact with the key players in viral internalization and replication such as angiotensin-converting enzyme 2 (ACE2), spike protein, the host transmembrane serine protease 2, and 3-chymotrypsin-like cysteine protease. In vitro data indicated that GR can interfere with virus entry by directly interacting with ACE2 and spike, with a nonspecific effect on cell and viral membranes. Additional anti-inflammatory and antioxidant effects of GR cannot be excluded. These multiple activities of GR and licorice extract are critically re-assessed in this review, and their possible role against the spread of the SARS-CoV-2 and the features of COVID-19 disease is discussed.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Ácido Glicirretínico/farmacologia , Ácido Glicirrízico/farmacologia , SARS-CoV-2/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , COVID-19/metabolismo , Ácido Glicirretínico/uso terapêutico , Glycyrrhiza/química , Ácido Glicirrízico/uso terapêutico , Humanos , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus/efeitos dos fármacos
14.
Molecules ; 26(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201422

RESUMO

A possible inhibitor of proteases, which contains an indole core and an aromatic polar acetylene, was designed and synthesized. This indole derivative has a molecular architecture kindred to biologically relevant species and was obtained through five synthetic steps with an overall yield of 37% from the 2,2'-(phenylazanediyl)di(ethan-1-ol). The indole derivative was evaluated through docking assays using the main protease (SARS-CoV-2-Mpro) as a molecular target, which plays a key role in the replication process of this virus. Additionally, the indole derivative was evaluated as an inhibitor of the enzyme kallikrein 5 (KLK5), which is a serine protease that can be considered as an anticancer drug target.


Assuntos
Acetileno/química , Antivirais/química , Antivirais/síntese química , Indóis/química , Inibidores de Proteases/química , Inibidores de Proteases/síntese química , SARS-CoV-2/enzimologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Descoberta de Drogas , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Calicreínas/antagonistas & inibidores , Modelos Moleculares , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos
15.
Molecules ; 26(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209485

RESUMO

(-)-Epigallocatechin-3-O-gallate (EGCG), the most abundant component of catechins in tea (Camellia sinensis (L.) O. Kuntze), plays a role against viruses through inhibiting virus invasiveness, restraining gene expression and replication. In this paper, the antiviral effects of EGCG on various viruses, including DNA virus, RNA virus, coronavirus, enterovirus and arbovirus, were reviewed. Meanwhile, the antiviral effects of the EGCG epi-isomer counterpart (+)-gallocatechin-3-O-gallate (GCG) were also discussed.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Catequina/análogos & derivados , Chá/química , Animais , Antivirais/uso terapêutico , Catequina/farmacologia , Catequina/uso terapêutico , Humanos , Internalização do Vírus/efeitos dos fármacos , Vírus/efeitos dos fármacos
16.
J Agric Food Chem ; 69(27): 7565-7571, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34210137

RESUMO

On the basis of our previous studies on the antiviral mechanism against tobacco mosaic virus (TMV) and structure-activity relationship of phenanthroindolizidine alkaloids, a series of 9-substituted tylophorine derivatives targeting TMV RNA were designed, synthesized, and assessed for their anti-TMV activities. The bioassay results indicated that most of these compounds showed good in vivo anti-TMV activities, and some of them displayed higher activity than that of commercial ribavirin. Especially, the anti-TMV activities of compound 3b, 4, and 6 are 2-3 times higher than that of commercial ribavirin, according to EC50 values. In this work, we have demonstrated an effective way to design new inhibitors against plant virus and developed 9-ethoxy methyl tylophorine (4) with excellent anti-TMV activity (in vitro activity, 70.2%/500 µg/mL and 27.1%/100 µg/mL; inactivation activity, 67.7%/500 µg/mL and 30.5%/100 µg/mL; curative activity, 65.3%/500 µg/mL and 30.8%/100 µg/mL; and protection activity, 65.9%/500 µg/mL and 36.0%/100 µg/mL) as a potential plant viral inhibitor.


Assuntos
Alcaloides , Vírus do Mosaico do Tabaco , Alcaloides/farmacologia , Antivirais/farmacologia , Desenho de Fármacos , Indolizinas , Fenantrolinas/farmacologia , Relação Estrutura-Atividade
17.
Sci Signal ; 14(690)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230209

RESUMO

Inorganic polyphosphates (polyPs) are linear polymers composed of repeated phosphate (PO4 3-) units linked together by multiple high-energy phosphoanhydride bonds. In addition to being a source of energy, polyPs have cytoprotective and antiviral activities. Here, we investigated the antiviral activities of long-chain polyPs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In molecular docking analyses, polyPs interacted with several conserved amino acid residues in angiotensin-converting enzyme 2 (ACE2), the host receptor that facilitates virus entry, and in viral RNA-dependent RNA polymerase (RdRp). ELISA and limited proteolysis assays using nano- LC-MS/MS mapped polyP120 binding to ACE2, and site-directed mutagenesis confirmed interactions between ACE2 and SARS-CoV-2 RdRp and identified the specific amino acid residues involved. PolyP120 enhanced the proteasomal degradation of both ACE2 and RdRp, thus impairing replication of the British B.1.1.7 SARS-CoV-2 variant. We thus tested polyPs for functional interactions with the virus in SARS-CoV-2-infected Vero E6 and Caco2 cells and in primary human nasal epithelial cells. Delivery of a nebulized form of polyP120 reduced the amounts of viral positive-sense genomic and subgenomic RNAs, of RNA transcripts encoding proinflammatory cytokines, and of viral structural proteins, thereby presenting SARS-CoV-2 infection in cells in vitro.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Polifosfatos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Administração por Inalação , Sequência de Aminoácidos , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antivirais/administração & dosagem , Antivirais/química , COVID-19/metabolismo , COVID-19/virologia , Células CACO-2 , Chlorocebus aethiops , RNA-Polimerase RNA-Dependente de Coronavírus/química , RNA-Polimerase RNA-Dependente de Coronavírus/genética , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Citocinas/metabolismo , Células HEK293 , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Técnicas In Vitro , Modelos Biológicos , Simulação de Acoplamento Molecular , Nebulizadores e Vaporizadores , Polifosfatos/administração & dosagem , Polifosfatos/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Domínios e Motivos de Interação entre Proteínas , Proteólise/efeitos dos fármacos , RNA Viral/genética , RNA Viral/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Homologia de Sequência de Aminoácidos , Transdução de Sinais/efeitos dos fármacos , Células Vero , Replicação Viral/efeitos dos fármacos
18.
Sci Adv ; 7(27)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34193418

RESUMO

The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates the rapid development of new therapies against coronavirus disease 2019 (COVID-19) infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced protein network, based on disease signatures defined by COVID-19 multiomics datasets, and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2-induced pathways, 40 of which are already in COVID-19 clinical trials, testifying to the validity of the approach. Using artificial neural network analysis, we classified these 200 drugs into nine distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (126) and immune response (74). Two drugs (proguanil and sulfasalazine) implicated in viral replication were shown to inhibit replication in cell assays. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.


Assuntos
Reposicionamento de Medicamentos , SARS-CoV-2/fisiologia , Antivirais/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Humanos , Redes Neurais de Computação , Proguanil/farmacologia , Proguanil/uso terapêutico , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Sulfassalazina/farmacologia , Replicação Viral/efeitos dos fármacos
19.
Molecules ; 26(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198817

RESUMO

Despite the serious public health problem represented by the diseases caused by dengue (DENV), Zika (ZIKV) and chikungunya (CHIKV) viruses, there are still no specific licensed antivirals available for their treatment. Here, we examined the potential anti-arbovirus activity of ten di-halogenated compounds derived from L-tyrosine with modifications in amine and carboxyl groups. The activity of compounds on VERO cell line infection and the possible mechanism of action of the most promising compounds were evaluated. Finally, molecular docking between the compounds and viral and cellular proteins was evaluated in silico with Autodock Vina®, and the molecular dynamic with Gromacs®. Only two compounds (TDC-2M-ME and TDB-2M-ME) inhibited both ZIKV and CHIKV. Within the possible mechanism, in CHIKV, the two compounds decreased the number of genome copies and in the pre-treatment strategy the infectious viral particles. In the ZIKV model, only TDB-2M-ME inhibited the viral protein and demonstrate a virucidal effect. Moreover, in the U937 cell line infected with CHIKV, both compounds inhibited the viral protein and TDB-2M-ME inhibited the viral genome too. Finally, the in silico results showed a favorable binding energy between the compounds and the helicases of both viral models, the NSP3 of CHIKV and cellular proteins DDC and ß2 adrenoreceptor.


Assuntos
Antivirais/síntese química , Vírus Chikungunya/efeitos dos fármacos , Vírus da Dengue/efeitos dos fármacos , Fenóis/síntese química , Tirosina/análogos & derivados , Zika virus/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Vírus Chikungunya/genética , Vírus Chikungunya/metabolismo , Chlorocebus aethiops , Vírus da Dengue/genética , Genoma Viral/efeitos dos fármacos , Halogenação , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Fenóis/química , Fenóis/farmacologia , Células Vero , Zika virus/genética , Zika virus/metabolismo
20.
Molecules ; 26(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199058

RESUMO

We measured and studied the growth parameters and the qualitative and quantitative composition of the flavones of hairy roots of the Scutellaria genus: S. lateriflora, S. przewalskii and S. pycnoclada. Hairy roots were obtained using wild-type Agrobacterium rhizogenes A4 by co-cultivation of explants (cotyledons) in a suspension of Agrobacterium. The presence of the rol-genes was confirmed by PCR analysis. The hairy roots of the most studied plant from the Scutellaria genus, S. baicalensis, were obtained earlier and used as a reference sample. HPLC-MS showed the predominance of four main flavones (baicalin, baicalein, wogonin and wogonoside) in the methanol extracts of the studied hairy roots. In addition to the four main flavones, the other substances which are typical to the aerial part of plants were found in all the extracts: apigenin, apigetrin, scutellarin and chrysin-7-O-ß-d-glucuronide. According to the total content of flavones, the hairy roots of the studied skullcaps form the following series: S. przewalskii (33 mg/g dry weight) > S. baicalensis (17.04 mg/g dry weight) > S. pycnoclada (12.9 mg/g dry weight) > S. lateriflora (4.57 mg/g dry weight). Therefore, the most promising producer of anti-coronavirus flavones is S. przewalskii.


Assuntos
Antivirais/química , Flavonas/química , Scutellaria/química , Agrobacterium/crescimento & desenvolvimento , Agrobacterium/metabolismo , Antivirais/isolamento & purificação , Antivirais/farmacologia , Cromatografia Líquida de Alta Pressão , Flavonas/isolamento & purificação , Flavonas/farmacologia , Células Vegetais/metabolismo , Extratos Vegetais/química , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Scutellaria/crescimento & desenvolvimento , Scutellaria/metabolismo , Espectrometria de Massas em Tandem
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