Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.101
Filtrar
1.
An Acad Bras Cienc ; 93(4): e20200632, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34586319

RESUMO

Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C. Sofosbuvir and simeprevir are prescribed worldwide. However, there is a scarcity of information regarding their genotoxicity. Therefore, the present study assessed the cytotoxic and genotoxic effects of sofosbuvir and simeprevir, alone and combined with ribavirin. HepG2 cells were analyzed using the in vitro cytokinesis-block micronucleus cytome assay. Cells were treated for 24 h with sofosbuvir (0.011-1.511 mM), simeprevir (0.156-5.0 µM), and their combinations with ribavirin (0.250-4.0 mM). No significant differences were observed in the nuclear division cytotoxicity index, reflecting the absence of cytotoxic effects associated to sofosbuvir. However, the highest concentration of simeprevir showed a significant difference for the nuclear division cytotoxicity index. Moreover, significant results were observed for nuclear division cytotoxicity index in two combinations of sofosbuvir plus ribavirin and only in the highest combination of simeprevir plus ribavirin. Additionally, our results showed that sofosbuvir did not increase the frequency of chromosomal damage, but simeprevir significantly increased the frequency of micronuclei at the highest concentrations. The combination index demonstrated that both sofosbuvir and simeprevir produced antagonism to the genotoxic effects of ribavirin. In conclusion, our results showed that simeprevir, but not sofosbuvir, has genotoxic effects in HepG2 cells.


Assuntos
Hepatite C Crônica , Simeprevir , Antivirais/toxicidade , Linhagem Celular , Quimioterapia Combinada , Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Humanos , Ribavirina/uso terapêutico , Ribavirina/toxicidade , Simeprevir/uso terapêutico , Simeprevir/toxicidade , Sofosbuvir/uso terapêutico , Sofosbuvir/toxicidade
2.
J Chem Inf Model ; 61(9): 4125-4130, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34516123

RESUMO

A recent publication in Science has proposed that cationic amphiphilic drugs repurposed for COVID-19 typically use phosholipidosis as their antiviral mechanism of action in cells but will have no in vivo efficacy. On the contrary, our viewpoint, supported by additional experimental data for similar cationic amphiphilic drugs, indicates that many of these molecules have both in vitro and in vivo efficacy with no reported phospholipidosis, and therefore, this class of compounds should not be avoided but further explored, as we continue the search for broad spectrum antivirals.


Assuntos
COVID-19 , Lipidoses , Preparações Farmacêuticas , Antivirais/toxicidade , Humanos , Lipidoses/tratamento farmacológico , Fosfolipídeos , SARS-CoV-2
3.
Bioorg Med Chem ; 46: 116364, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34450570

RESUMO

The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19. However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Herein, we reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two l-valine esters, and one carbamate. Among the new nucleosides, only the 7-fluoro analog 3c had moderate anti-SARS-CoV-2 activity, and its phosphoramidate prodrug 7 exhibited reduced activity in Vero E6 cells. As for the prodrugs, the 3'-isobutyryl ester 5a, the 5'-isobutyryl ester 5c, and the tri-isobutyryl ester 5g hydrobromide showed excellent oral bioavailabilities (F = 71.6%, 86.6% and 98.7%, respectively) in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.


Assuntos
Adenosina/análogos & derivados , Antivirais/farmacologia , SARS-CoV-2/efeitos dos fármacos , Adenosina/farmacocinética , Adenosina/farmacologia , Adenosina/toxicidade , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Antivirais/toxicidade , Chlorocebus aethiops , Masculino , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Pró-Fármacos/toxicidade , Células Vero
4.
Bioorg Chem ; 115: 105196, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34333425

RESUMO

So far, there is still no specific drug against COVID-19. Taking compound 1 with anti-EBOV activity as the lead, fifty-four 12N-substituted aloperine derivatives were synthesized and evaluated for the anti-SARS-CoV-2 activities using pseudotyped virus model. Among them, 8a exhibited the most potential effects against both pseudotyped and authentic SARS-CoV-2, as well as SARS-CoV and MERS-CoV, indicating a broad-spectrum anti-coronavirus profile. The mechanism study disclosed that 8a might block a late stage of viral entry, mainly via inhibiting host cathepsin B activity rather than directly targeting cathepsin B protein. Also, 8a could significantly reduce the release of multiple inflammatory cytokines in a time- and dose-dependent manner, such as IL-6, IL-1ß, IL-8 and MCP-1, the major contributors to cytokine storm. Therefore, 8a is a promising agent with the advantages of broad-spectrum anti-coronavirus and anti-cytokine effects, thus worthy of further investigation.


Assuntos
Antivirais/farmacologia , Piperidinas/farmacologia , Quinolizidinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Antivirais/toxicidade , Catepsina B/antagonistas & inibidores , Chlorocebus aethiops , Citocinas/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/farmacocinética , Piperidinas/toxicidade , Quinolizidinas/síntese química , Quinolizidinas/farmacocinética , Quinolizidinas/toxicidade , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Células Vero
5.
Science ; 373(6554): 541-547, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34326236

RESUMO

Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs we tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs and does not reflect specific target-based activities-rather, it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Lipidoses/induzido quimicamente , Fosfolipídeos/metabolismo , SARS-CoV-2/efeitos dos fármacos , Células A549 , Animais , Antivirais/química , Antivirais/uso terapêutico , Antivirais/toxicidade , COVID-19/virologia , Cátions , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Testes de Sensibilidade Microbiana , SARS-CoV-2/fisiologia , Tensoativos/química , Tensoativos/farmacologia , Tensoativos/toxicidade , Células Vero , Replicação Viral/efeitos dos fármacos
6.
SAR QSAR Environ Res ; 32(8): 643-654, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34282674

RESUMO

Influenza affects millions of people globally and the appearance of drug-resistant strains is an ongoing problem. Therefore, this work reports the development of quantitative structure-activity relationship (QSAR) models to predict some biological properties of new 2-iminobenzimidazoline candidates for the treatment of the flu. A series of 2-iminobenzimidazoline derivatives with experimentally available values for cytotoxicity (pCC50) and anti-influenza activity (pIC50) was used for multivariate image analysis applied to QSAR (MIA-QSAR). The models were vigorously validated according to the best practices in QSAR and the chemical features responsible for the response variables were analysed based on MIA-plots, which assess the PLS regression coefficients and variable importance in projection scores. MIA descriptors encoding atomic properties (van der Waals radius and electronegativity) were capable of properly modelling the pCC50 and pIC50 data. The internally and externally validated models were used to predict the selectivity indexes (SI = pCC50/pIC50) of unprecedented analogues, which were designed upon analysis of the MIA-plots that show the substituent groups most affecting the biological data and by the combination of substructures of selected molecules. At least three promising anti-influenza candidates could be proposed from the predictive MIA-QSAR models.


Assuntos
Antivirais/química , Antivirais/farmacologia , Benzimidazóis/química , Relação Quantitativa Estrutura-Atividade , Antivirais/toxicidade , Benzimidazóis/farmacologia , Bases de Dados de Produtos Farmacêuticos , Humanos , Ligação de Hidrogênio , Influenza Humana/tratamento farmacológico
7.
Xenobiotica ; 51(9): 1047-1059, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34319859

RESUMO

Podophyllotoxin (POD) is a natural compound with antiviral and anticancer activities. The purpose of the present study was to determine the metabolic map of POD in vitro and in vivo.Mouse and human liver microsomes were employed to identify POD metabolites in vitro and recombinant drug-metabolizing enzymes were used to identify the mono-oxygenase enzymes involved in POD metabolism. All in vitro incubation mixtures and bile samples from mice treated with POD were analysed with ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry.A total of 38metabolites, including six phase-I metabolites and 32 phase-II metabolites, of POD were identified from bile and faeces samples after oral administration, and their structures were elucidated through interpreting MS/MS fragmentation patterns.Nine metabolites, including two phase-I metabolites, five glucuronide conjugates, and two GSH conjugates were detected in both human and mouse liver microsome incubation systems and the generation of all metabolites were NADPH-dependent. The main phase-I enzymes involved in metabolism of POD in vitro include CYP2C9, CYP2C19, CYP3A4, and CYP3A5.POD administration to mice caused hepatic and intestinal toxicity, and the cellular damage was exacerbated when 1-aminobenzotriazole, a broad-spectrum inhibitor of CYPs, was administered with POD, indicating that POD, but not its metabolites, induced hepatic and intestinal toxicities.This study elucidated the metabolic map and provides important reference basis for the safety evaluation and rational for the clinical application of POD.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Espectrometria de Massas em Tandem , Animais , Antivirais/toxicidade , Cromatografia Líquida de Alta Pressão , Camundongos , Microssomos Hepáticos , Podofilotoxina
8.
Drugs R D ; 21(3): 273-283, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34324175

RESUMO

BACKGROUND AND OBJECTIVE: Coronavirus disease 2019 is a novel disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus. It was first detected in December 2019 and has since been declared a pandemic causing millions of deaths worldwide. Therefore, there is an urgent need to develop effective therapeutics against coronavirus disease 2019. A critical step in the crosstalk between the virus and the host cell is the binding of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to the peptidase domain of the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of host cells. METHODS: An in silico approach was employed to design a 13-amino acid peptide inhibitor (13AApi) against the RBD of the SARS-CoV-2 spike protein. Its binding specificity for RBD was confirmed by molecular docking using pyDockWEB, ClusPro 2.0, and HDOCK web servers. The stability of 13AApi and the SARS-CoV-2 spike protein complex was determined by molecular dynamics simulation using the GROMACS program while the physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of 13AApi were determined using the ExPASy tool and pkCSM server. Finally, in vitro validation of the inhibitory activity of 13AApi against the spike protein was performed by an enzyme-linked immunosorbent assay. RESULTS: In silico analyses indicated that the 13AApi could bind to the RBD of the SARS-CoV-2 spike protein at the ACE2 binding site with high affinity. In vitro experiments validated the in silico findings, showing that 13AApi could significantly block the RBD of the SARS-CoV-2 spike protein. CONCLUSIONS: Blockage of binding of the SARS-CoV-2 spike protein with ACE2 in the presence of the 13AApi may prevent virus entry into host cells. Therefore, the 13AApi can be utilized as a promising therapeutic agent to combat coronavirus disease 2019.


Assuntos
Enzima de Conversão de Angiotensina 2/efeitos dos fármacos , Antivirais/farmacologia , Peptídeos/farmacologia , Glicoproteína da Espícula de Coronavírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/farmacocinética , Antivirais/toxicidade , Sítios de Ligação , Simulação por Computador , Desenho de Fármacos , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Peptídeos/farmacocinética , Peptídeos/toxicidade , Ligação Proteica/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Especificidade por Substrato
9.
Phytomedicine ; 87: 153591, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34029937

RESUMO

BACKGROUND: The outbreak of coronavirus (SARS-CoV-2) disease caused more than 100,000,000 people get infected and over 2,200,000 people being killed worldwide. However, the current developed vaccines or drugs may be not effective in preventing the pandemic of COVID-19 due to the mutations of coronavirus and the severe side effects of the newly developed vaccines. Chinese herbal medicines and their active components play important antiviral activities. Corilagin exhibited antiviral effect on human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Epstein-Barr virus (EBV). However, whether it blocks the interaction between SARS-CoV-2 RBD and hACE2 has not been elucidated. PURPOSE: To characterize an active compound, corilagin derived from Phyllanthus urinaria as potential SARS-CoV-2 entry inhibitors for its possible preventive application in daily anti-virus hygienic products. METHODS: Computational docking coupled with bio-layer interferometry, BLI were adopted to screen more than 1800 natural compounds for the identification of SARS-CoV-2 spike-RBD inhibitors. Corilagin was confirmed to have a strong binding affinity with SARS-CoV-2-RBD or human ACE2 (hACE2) protein by the BLI, ELISA and immunocytochemistry (ICC) assay. Furthermore, the inhibitory effect of viral infection of corilagin was assessed by in vitro pseudovirus system. Finally, the toxicity of corilagin was examined by using MTT assay and maximal tolerated dose (MTD) studies in C57BL/6 mice. RESULTS: Corilagin preferentially binds to a pocket that contains residues Cys 336 to Phe 374 of spike-RBD with a relatively low binding energy of -9.4 kcal/mol. BLI assay further confirmed that corilagin exhibits a relatively strong binding affinity to SARS-CoV-2-RBD and hACE2 protein. In addition, corilagin dose-dependently blocks SARS-CoV-2-RBD binding and abolishes the infectious property of RBD-pseudotyped lentivirus in hACE2 overexpressing HEK293 cells, which mimicked the entry of SARS-CoV-2 virus in human host cells. Finally, in vivo studies revealed that up to 300 mg/kg/day of corilagin was safe in C57BL/6 mice. Our findings suggest that corilagin could be a safe and potential antiviral agent against the COVID-19 acting through the blockade of the fusion of SARS-CoV-2 spike-RBD to hACE2 receptors. CONCLUSION: Corilagin could be considered as a safe and environmental friendly anti-SARS-CoV-2 agent for its potential preventive application in daily anti-virus hygienic products.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/farmacologia , Glucosídeos/farmacologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Taninos Hidrolisáveis/farmacologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/química , Animais , Antivirais/química , Antivirais/toxicidade , COVID-19 , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Glucosídeos/química , Glucosídeos/toxicidade , Células HEK293 , Humanos , Taninos Hidrolisáveis/química , Taninos Hidrolisáveis/toxicidade , Infecções por Lentivirus/tratamento farmacológico , Masculino , Dose Máxima Tolerável , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Glicoproteína da Espícula de Coronavírus/química
10.
Eur J Med Chem ; 220: 113467, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33894564

RESUMO

Emerging and re-emerging viruses periodically cause outbreaks and epidemics all over the world, eventually leading to global events such as the current pandemic of the novel SARS-CoV-2 coronavirus infection COVID-19. Therefore, an urgent need for novel antivirals is crystal clear. Here we present the synthesis and evaluation of an antiviral activity of phenoxazine-based nucleoside analogs divided into three groups: (1) 8-alkoxy-substituted, (2) acyclic, and (3) carbocyclic. The antiviral activity was assessed against a structurally and phylogenetically diverse panel of RNA and DNA viruses from 25 species. Four compounds (11a-c, 12c) inhibited 4 DNA/RNA viruses with EC50 ≤ 20 µM. Toxicity of the compounds for the cell lines used for virus cultivation was negligible in most cases. In addition, previously reported and newly synthesized phenoxazine derivatives were evaluated against SARS-CoV-2, and some of them showed promising inhibition of reproduction with EC50 values in low micromolar range, although accompanied by commensurate cytotoxicity.


Assuntos
Antivirais/farmacologia , Vírus de DNA/efeitos dos fármacos , Nucleosídeos/farmacologia , Oxazinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/toxicidade , Linhagem Celular Tumoral , Chlorocebus aethiops , Cães , Humanos , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/toxicidade , Oxazinas/síntese química , Oxazinas/toxicidade , Relação Estrutura-Atividade , Células Vero , Replicação Viral/efeitos dos fármacos
11.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921228

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC50 values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC50 values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs.


Assuntos
Antivirais/química , Antivirais/metabolismo , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , SARS-CoV-2/enzimologia , Animais , Antivirais/toxicidade , Simulação por Computador , Cristalografia por Raios X , Bases de Dados de Compostos Químicos , Bases de Dados de Proteínas , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Dose Letal Mediana , Ligantes , Testes de Mutagenicidade , Inibidores de Proteases/toxicidade , Relação Quantitativa Estrutura-Atividade , Ratos , Ubiquitina Tiolesterase/química , Ubiquitina Tiolesterase/metabolismo
12.
Molecules ; 26(5)2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33800013

RESUMO

With the emergence and global spread of the COVID-19 pandemic, the scientific community worldwide has focused on search for new therapeutic strategies against this disease. One such critical approach is targeting proteins such as helicases that regulate most of the SARS-CoV-2 RNA metabolism. The purpose of the current study was to predict a library of phytochemicals derived from diverse plant families with high binding affinity to SARS-CoV-2 helicase (Nsp13) enzyme. High throughput virtual screening of the Medicinal Plant Database for Drug Design (MPD3) database was performed on SARS-CoV-2 helicase using AutoDock Vina. Nilotinib, with a docking value of -9.6 kcal/mol, was chosen as a reference molecule. A compound (PubChem CID: 110143421, ZINC database ID: ZINC257223845, eMolecules: 43290531) was screened as the best binder (binding energy of -10.2 kcal/mol on average) to the enzyme by using repeated docking runs in the screening process. On inspection, the compound was disclosed to show different binding sites of the triangular pockets collectively formed by Rec1A, Rec2A, and 1B domains and a stalk domain at the base. The molecule is often bound to the ATP binding site (referred to as binding site 2) of the helicase enzyme. The compound was further discovered to fulfill drug-likeness and lead-likeness criteria, have good physicochemical and pharmacokinetics properties, and to be non-toxic. Molecular dynamic simulation analysis of the control/lead compound complexes demonstrated the formation of stable complexes with good intermolecular binding affinity. Lastly, affirmation of the docking simulation studies was accomplished by estimating the binding free energy by MMPB/GBSA technique. Taken together, these findings present further in silco investigation of plant-derived lead compounds to effectively address COVID-19.


Assuntos
Metiltransferases/antagonistas & inibidores , Metiltransferases/metabolismo , RNA Helicases/antagonistas & inibidores , RNA Helicases/metabolismo , SARS-CoV-2/enzimologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacocinética , Antivirais/toxicidade , Sítios de Ligação , Disponibilidade Biológica , COVID-19/tratamento farmacológico , Biologia Computacional/métodos , Bases de Dados de Compostos Químicos , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Metiltransferases/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/metabolismo , Plantas Medicinais/química , Ligação Proteica , Domínios Proteicos/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/toxicidade , RNA Helicases/química , Relação Estrutura-Atividade , Termodinâmica , Proteínas não Estruturais Virais/química
13.
Biomolecules ; 11(3)2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808721

RESUMO

The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (Mpro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) has been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = -8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = -6.49 kcal/mol), and nsp10 (ΔG = -9.06 kcal/mol). Compound 13 showed promising binding affinities against Mpro (ΔG = -7.99 kcal/mol), spike glycoproteins (ΔG = -6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = -8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD50, rat maximum tolerated dose, rat oral LD50, and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds, 5 and 13, with their targets. In conclusion, the examined 15 alkaloids specially 5 and 13 showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2.


Assuntos
Alcaloides/química , Antivirais/química , Proteínas do Nucleocapsídeo de Coronavírus/química , Poríferos/química , SARS-CoV-2/química , Glicoproteína da Espícula de Coronavírus/química , Animais , Antivirais/farmacologia , Antivirais/toxicidade , Barreira Hematoencefálica , Cristalografia por Raios X , Ligantes , Glicoproteínas de Membrana/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fosfoproteínas/química , Inibidores de Proteases/química , Ratos , Software , Proteases Virais/química
14.
Sci Total Environ ; 776: 145740, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33647647

RESUMO

Antiviral drugs have been used to treat the ever-growing number of coronavirus disease, 2019 (COVID-19) patients. Consequently, unprecedented amounts of such drug residues discharging into ambient waters raise concerns on the potential ecotoxicological effects to aquatic lives, as well as development of antiviral drug-resistance in wildlife. Here, we estimated the occurrence, fate and ecotoxicological risk of 11 therapeutic agents suggested as drugs for COVID-19 treatment and their 13 metabolites in wastewater and environmental waters, based on drug consumption, physical-chemical property, and ecotoxicological and pharmacological data for the drugs, with the aid of quantitative structure-activity relationship (QSAR) modelling. Our results suggest that the removal efficiencies at conventional wastewater treatment plants will remain low (<20%) for half of the substances, and consequently, high drug residues (e.g. 7402 ng/L ribavirin, 4231 ng/L favipiravir, 730 ng/L lopinavir, 319 ng/L remdesivir; each combined for both unchanged forms and metabolites; and when each drug is administered to 100 patients out of 100,000 populations on a day) can be present in secondary effluents and persist in the environmental waters. Ecotoxicological risk in receiving river waters can be high (risk quotient >1) by a use of favipiravir, lopinavir, umifenovir and ritonavir, and medium (risk quotient >0.1) by a use of chloroquine, hydroxychloroquine, remdesivir, and ribavirin, while the risk will remain low (risk quotient <0.1) for dexamethasone and oseltamivir. The potential of wild animals acquiring antiviral drug resistance was estimated to be low. Our prediction suggests a pressing need for proper usage and waste management of antiviral drugs as well as for improving removal efficiencies of drug residues in wastewater.


Assuntos
COVID-19 , Coronavirus , Animais , Antivirais/toxicidade , COVID-19/tratamento farmacológico , Humanos , SARS-CoV-2
15.
J Ethnopharmacol ; 272: 113954, 2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-33610706

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Andrographis paniculata (Burm.f.) Nees is widely used all over the world, especially in subtropical regions such as India, Thailand, Vietnam, and China. As a traditional folk Chinese medicine, A. paniculata has been extensively utilized for the treatment of cold, fever, sore throat, cough, carbuncle, and sores, and it is commonly employed for 'clearing heat and resolving toxicity'. Typical symptoms of 'heat and toxicity' include swollen, painful gums, associated with virus-related diseases to a great extent. In vivo and in vitro experiments have demonstrated the potential antiviral properties of A. paniculata and identified its major active constituents against various viruses. AIM OF THE STUDY: This review focuses on connecting the traditional 'clearing heat and resolving toxicity' effect to compelling recent research advances on the antiviral effects of A. paniculata, explaining its major antiviral mechanisms, and assessing the shortcomings of existing work. Besides, ethnobotany, ethnopharmacological uses, phytochemicals, and toxicology of A. paniculata have been researched. MATERIALS AND METHODS: The information about A. paniculata was collected from various sources including classic books about Chinese herbal medicine, and scientific databases including WEB OF SCIENCE, PubMed, ScienceDirect, Springer, ACS, SCOPUS, CNKI, CSTJ, and WANFANG. RESULTS: In this review, the underlying mechanisms of antiviral effect mainly involve the regulation of virus entry, gene replication, and synthesis of functionally mature proteins. Also, A. paniculata is a safe agent without obvious toxicity. Ethnobotany, ethnopharmacological uses, and chemical constituents have been summarized. CONCLUSION: Andrographis paniculata (Burm.f.) Nees could be used as an imperative complementary medicine for the treatment of diverse virus infection, efforts should be made to gain insights into its antiviral properties.


Assuntos
Andrographis/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Antivirais/toxicidade , Ásia , Diterpenos/toxicidade , Etnofarmacologia , Humanos , Compostos Fitoquímicos/química , Extratos Vegetais/toxicidade
16.
BMC Complement Med Ther ; 21(1): 27, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33435968

RESUMO

BACKGROUND: New agents for developing alternative or complementary medicine to treat the hepatitis C virus (HCV) are still needed due to high rates of HCV infection globally and the current limitations of available treatments. Treatment of HCV with a combination of direct acting antivirals have been shown to be approximately 90% effective but will be limited in the future due to the emergence of drug resistance and high cost. The leaves of Melicope latifolia have previously been reported to have anti-HCV activity and are a potential source of bioactive compounds for future novel drug development. This study aimed to evaluate the efficacy of the extract of M. latifolia fruit to treat HCV and to isolate its active compounds. METHOD: M. latifolia fruit was extracted using methanol and purified using vacuum liquid chromatography (VLC) and Radial Chromatography. The anti-HCV activity was analyzed using cell culture lines Huh7it-1 and JFH1 (genotype 2a). Time-of-addition and immunoblotting studies were performed to identify the mode of action of the isolated active compounds. The structures of the active compounds were determined using nuclear magnetic resonance (NMR) spectra, UV, IR, and Mass Spectra. RESULTS: Six known compounds were isolated from M. latifolia fruit: O-methyloktadrenolon, alloevodionol, isopimpinellin, alloxanthoxyletin, methylevodionol, and N-methylflindersine. N-methylflidersine was the most active compound with IC50 value of 3.8 µg/ml while methylevodionol, isopimpinellin, and alloevodionol were less active. O-methyloktadrenolon and alloxanthoxyletin were moderately active with IC50 values of 10.9 and 21.72 µg/ml, respectively. N-methylflidersine decreased level of HCV NS3 protein expression in the cells. CONCLUSION: The alkaloid compound, N-methylflindersine which was isolated from M. latifolia possesses anti-HCV activity through post-entry inhibition and suppressed NS3 protein expression.


Assuntos
Alcaloides/farmacologia , Antivirais/farmacologia , Benzopiranos/farmacologia , Hepacivirus/efeitos dos fármacos , Rutaceae/química , Alcaloides/química , Alcaloides/toxicidade , Antivirais/química , Antivirais/toxicidade , Benzopiranos/química , Benzopiranos/toxicidade , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Frutas/química , Hepatite C/virologia , Humanos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/toxicidade
17.
J Ethnopharmacol ; 271: 113878, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33515683

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ricinus communis L., commonly known as castor oil plant, is a precious traditional medicine with a history of thousands of years in the world. Castor oil plant has high traditional and medicinal values for treating liver infections, stomach ache, flatulence, constipation, inflammation, warts, colic, enteritis, fever, headache, and as a counter irritant. Its diverse phytochemicals have a wide range of valuable medicinal activities including hepatoprotective, anti-nociceptive, antioxidant, antiulcer, anticancer, anti-inflammatory, central analgesic, antidiabetic, antimicrobial, antiviral, and wound healing activity. AIM OF THE WORK: To provide a complete characterization of the composition of Ricinus communis leaves using ultra-performance liquid chromatography coupled with hybrid triple time-of-flight mass spectrometry (UPLC-Triple TOF-MS/MS) and different chromatographic techniques and to evaluate its antiviral potential using three mechanisms against three common viruses. MATERIALS AND METHODS: R. communis leaves were extracted with 70% methanol and further partitioned with solvents of increasing polarities: petroleum ether, dichloromethane (CH2Cl2), ethyl acetate, and n-butanol. The CH2Cl2 and n-butanol fractions were subjected to repeated chromatographic separation to isolate the phytochemicals, and their structures were elucidated using nuclear magnetic resonance spectroscopy. UPLC-Triple TOF-MS/MS was performed to determine the different phytochemicals in the ethyl acetate fraction. The antiviral activity of the extracts was investigated using the maximum nontoxic concentration of each against the challenge dose of the virus (CDV) and 1/10 and 1/100 dilutions of the CDV for Coxsackie B virus type 4 (COXB4), herpes simplex virus type 1 (HSV1), and hepatitis A virus (HAV) using Vero cell cultures that were treated according to three protocols to test for anti-replicative, protective, and anti-infective antiviral activity. Cell viability was evaluated using the MTT colorimetric assay and each experiment is repeated three times independently of each other. RESULTS: R. communis leaves possessed antiviral activity. Evaluation of the anti-replicative activity showed that all extracts possessed high anti-replicative activity against HAV especially methanol and methylene chloride fractions and moderate activity against COXB4; butanol > methylene chloride and ethyl acetate > methanol. All extracts showed protective activity against HAV, especially butanol extract, while methanol extracts showed higher non-significant antiviral protective activity against HSV1 vs Acyclovir. Almost no anti-infective effects were recorded for any extract against the studied viruses. CONCLUSION: The discriminatory effect against each virus by different mechanisms suggests the presence of different chemical compounds. The alkaloid and phenolic derivatives of the extracts of R. communis leaves may help develop a drug to prevent or treat common viral infections. Further investigations are recommended to define the bioactive antiviral properties of R. communis leaves.


Assuntos
Antivirais/farmacologia , Extratos Vegetais/farmacologia , Ricinus/química , Aciclovir/farmacologia , Aciclovir/toxicidade , Animais , Antivirais/isolamento & purificação , Antivirais/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cromatografia Líquida de Alta Pressão , Medicina Tradicional , Metanol/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Folhas de Planta/química , Solventes/química , Espectrometria de Massas em Tandem , Células Vero , Vírus/efeitos dos fármacos
18.
J Ethnopharmacol ; 273: 113871, 2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-33485971

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Reduning injection (RDNI) is a patented Traditional Chinese medicine that contains three Chinese herbal medicines, respectively are the dry aboveground part of Artemisia annua L., the flower of Lonicera japonica Thunb., and the fruit Gardenia jasminoides J.Ellis. RDNI has been recommended for treating Coronavirus Disease 2019 (COVID-19) in the "New Coronavirus Pneumonia Diagnosis and Treatment Plan". AIM OF THE STUDY: To elucidate and verify the underlying mechanisms of RDNI for the treatment of COVID-19. METHODS: This study firstly performed anti-SARS-CoV-2 experiments in Vero E6 cells. Then, network pharmacology combined with molecular docking was adopted to explore the potential mechanisms of RDNI in the treatment for COVID-19. After that, western blot and a cytokine chip were used to validate the predictive results. RESULTS: We concluded that half toxic concentration of drug CC50 (dilution ratio) = 1:1280, CC50 = 2.031 mg crude drugs/mL (0.047 mg solid content/mL) and half effective concentration of drug (EC50) (diluted multiples) = 1:25140.3, EC50 = 103.420 µg crude drugs/mL (2.405 µg solid content/mL). We found that RDNI can mainly regulate targets like carbonic anhydrases (CAs), matrix metallopeptidases (MMPs) and pathways like PI3K/AKT, MAPK, Forkhead box O s and T cell receptor signaling pathways to reduce lung damage. We verified that RDNI could effectively inhibit the overexpression of MAPKs, PKC and p65 nuclear factor-κB. The injection could also affect cytokine levels, reduce inflammation and display antipyretic activity. CONCLUSION: RDNI can regulate ACE2, Mpro and PLP in COVID-19. The underlying mechanisms of RDNI in the treatment for COVID-19 may be related to the modulation of the cytokine levels and inflammation and its antipyretic activity by regulating the expression of MAPKs, PKC and p65 nuclear factor NF-κB.


Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antivirais/química , Antivirais/toxicidade , Linhagem Celular Transformada , Chlorocebus aethiops , Biologia Computacional , Proteases 3C de Coronavírus/metabolismo , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Citocinas/metabolismo , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/toxicidade , Humanos , Medicina Tradicional Chinesa/métodos , Simulação de Acoplamento Molecular , Análise Serial de Proteínas , SARS-CoV-2/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células Vero
19.
Angew Chem Int Ed Engl ; 60(11): 6101-6106, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33241871

RESUMO

The entry of enveloped virus requires the fusion of viral and host cell membranes. An effective fusion inhibitor aiming at impeding such membrane fusion may emerge as a broad-spectrum antiviral agent against a wide range of viral infections. Mycobacterium survives inside the phagosome by inhibiting phagosome-lysosome fusion with the help of a coat protein coronin 1. Structural analysis of coronin 1 and other WD40-repeat protein suggest that the trp-asp (WD) sequence is placed at distorted ß-meander motif (more exposed) in coronin 1. The unique structural feature of coronin 1 was explored to identify a simple lipo-peptide sequence (myr-WD), which effectively inhibits membrane fusion by modulating the interfacial order, water penetration, and surface potential. The mycobacterium inspired lipo-dipeptide was successfully tested to combat type 1 influenza virus (H1N1) and murine coronavirus infections as a potential broad-spectrum antiviral agent.


Assuntos
Antivirais/farmacologia , Dipeptídeos/farmacologia , Lipopeptídeos/farmacologia , Fusão de Membrana/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/toxicidade , Dipeptídeos/química , Dipeptídeos/toxicidade , Cães , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Lipopeptídeos/química , Lipopeptídeos/toxicidade , Lipossomos/química , Células Madin Darby de Rim Canino , Vírus da Hepatite Murina/efeitos dos fármacos , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Ratos
20.
Comb Chem High Throughput Screen ; 24(6): 879-890, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32819226

RESUMO

BACKGROUND: COVID-19 is a pandemic respiratory contagious viral (SARS-CoV-2) disease associated with high morbidity and mortality worldwide. Currently, there are no effective preventive or treatment strategies for COVID-19 and it has been declared as a global health emergency by WHO. In silico molecular docking studies can be useful to predict the binding affinity between the phytocompound and the target protein and play a vital role in finding an inhibitor through structure-based drug design. OBJECTIVE: In this aspect, our objective was to screen essential flavonoids against possible protein targets such as SARS-CoV-2 spike glycoprotein receptor binding domain (RBD-S) and host Angiotensin Converting Enzyme-2 protease domain (PD-ACE-2) using in silico molecular docking studies. METHODS: Approximately 49 flavonoids were identified and were evaluated for their drug-likeness based on Lipinski rule, bioactivity scores, antiviral and toxicity profiles using SwissADME, Molinspiration, PASS and GUSAR online tools. The flavonoids that passed Lipinski rule were subjected to in silico analysis through molecular docking on RBD-S and PD-ACE-2 using Molegro Virtual Docker v6.0. RESULTS: The bioactive flavonoids that showed NIL violations and were found in compliance with Lipinski rule were selected for docking studies. In silico analysis reported that biochanin A and silymarin bind significantly at the active sites of RBD-S and PD-ACE-2 with a MolDock score of -78.41and -121.28 kcal/mol respectively. Bioactivity scores, antiviral potential and toxicity profiles were predicted for the top interacting phytocompounds and substantial relevant data was reported. CONCLUSION: The current outcomes created a new paradigm for understanding biochanin A and silymarin bioflavonoids as potent inhibitors of RBD-S and PD-ACE-2 targets respectively. Further work can be extended to confirm their therapeutic potential for COVID-19.


Assuntos
Antivirais/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Flavonoides/farmacologia , SARS-CoV-2/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antivirais/química , Antivirais/toxicidade , Sítios de Ligação , Simulação por Computador , Flavonoides/química , Flavonoides/toxicidade , Simulação de Acoplamento Molecular , Domínios Proteicos , Ratos , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...