Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28.778
Filtrar
1.
Molecules ; 27(1)2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-35011492

RESUMO

Before entering the cell, the SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) binds to the human angiotensin-converting enzyme 2 (hACE2) receptor. Hence, this RBD is a critical target for the development of antiviral agents. Recent studies have discovered that SARS-CoV-2 variants with mutations in the RBD have spread globally. The purpose of this in silico study was to determine the potential of a fruit bromelain-derived peptide. DYGAVNEVK. to inhibit the entry of various SARS-CoV-2 variants into human cells by targeting the hACE binding site within the RBD. Molecular docking analysis revealed that DYGAVNEVK interacts with several critical RBD binding residues responsible for the adhesion of the RBD to hACE2. Moreover, 100 ns MD simulations revealed stable interactions between DYGAVNEVK and RBD variants derived from the trajectory of root-mean-square deviation (RMSD), radius of gyration (Rg), and root-mean-square fluctuation (RMSF) analysis, as well as free binding energy calculations. Overall, our computational results indicate that DYGAVNEVK warrants further investigation as a candidate for preventing SARS-CoV-2 due to its interaction with the RBD of SARS-CoV-2 variants.


Assuntos
Enzima de Conversão de Angiotensina 2 , Bromelaínas , Simulação por Computador , Domínios e Motivos de Interação entre Proteínas , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/química , Antivirais/química , Antivirais/farmacologia , Bromelaínas/química , Bromelaínas/farmacologia , COVID-19/tratamento farmacológico , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptídeos/química , Peptídeos/farmacologia , Ligação Proteica , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/química
2.
Molecules ; 27(1)2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-35011529

RESUMO

When developing drugs against SARS-CoV-2, it is important to consider the characteristics of patients with different co-morbidities. People infected with HIV-1 are a particularly vulnerable group, as they may be at a higher risk than the general population of contracting COVID-19 with clinical complications. For such patients, drugs with a broad spectrum of antiviral activity are of paramount importance. Glycyrrhizinic acid (Glyc) and its derivatives are promising biologically active compounds for the development of such broad-spectrum antiviral agents. In this work, derivatives of Glyc obtained by acylation with nicotinic acid were investigated. The resulting preparation, Glycyvir, is a multi-component mixture containing mainly mono-, di-, tri- and tetranicotinates. The composition of Glycyvir was characterized by HPLC-MS/MS and its toxicity assessed in cell culture. Antiviral activity against three strains of SARS-CoV-2 was tested in vitro on Vero E6 cells by MTT assay. Glycyvir was shown to inhibit SARS-CoV-2 replication in vitro (IC502-8 µM) with an antiviral activity comparable to the control drug Remdesivir. In addition, Glycyvir exhibited marked inhibitory activity against HIV pseudoviruses of subtypes B, A6 and the recombinant form CRF63_02A (IC50 range 3.9-27.5 µM). The time-dependence of Glycyvir inhibitory activity on HIV pseudovirus infection of TZM-bl cells suggested that the compound interfered with virus entry into the target cell. Glycyvir is a promising candidate as an agent with low toxicity and a broad spectrum of antiviral action.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Ácido Glicirrízico/química , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Replicação Viral , Animais , Antivirais/síntese química , COVID-19/virologia , Chlorocebus aethiops , Infecções por HIV/virologia , Células HeLa , Humanos , Técnicas In Vitro , Células Vero
3.
Cell Mol Life Sci ; 79(1): 65, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013790

RESUMO

Coronavirus disease 2019 (COVID-19), the illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 260 million confirmed infections and 5 million deaths to date. While vaccination is a powerful tool to control pandemic spread, medication to relieve COVID-19-associated symptoms and alleviate disease progression especially in high-risk patients is still lacking. In this study, we explore the suitability of the rapid accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway as a druggable target in the treatment of SARS-CoV-2 infections. We find that SARS-CoV-2 transiently activates Raf/MEK/ERK signaling in the very early infection phase and that ERK1/2 knockdown limits virus replication in cell culture models. We demonstrate that ATR-002, a specific inhibitor of the upstream MEK1/2 kinases which is currently evaluated in clinical trials as an anti-influenza drug, displays strong anti-SARS-CoV-2 activity in cell lines as well as in primary air-liquid-interphase epithelial cell (ALI) cultures, with a safe and selective treatment window. We also observe that ATR-002 treatment impairs the SARS-CoV-2-induced expression of pro-inflammatory cytokines, and thus might prevent COVID-19-associated hyperinflammation, a key player in COVID-19 progression. Thus, our data suggest that the Raf/MEK/ERK signaling cascade may represent a target for therapeutic intervention strategies against SARS-CoV-2 infections and that ATR-002 is a promising candidate for further drug evaluation.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Fenamatos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , SARS-CoV-2/efeitos dos fármacos , Células A549 , Adulto , Animais , COVID-19/metabolismo , Linhagem Celular , Células Cultivadas , Chlorocebus aethiops , Citocinas/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/metabolismo , SARS-CoV-2/fisiologia , Células Vero , Replicação Viral/efeitos dos fármacos
4.
Nihon Yakurigaku Zasshi ; 157(1): 27-30, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-34980807

RESUMO

The new coronavirus (SARS-CoV-2) spread throughout the world and caused a pandemic with COVID-19, an infection caused by SARS-CoV-2. Even today, an increase in the number of cases has also been observed in Japan. Since the drugs used in drug repositioning have already been tested for safety and pharmacokinetics in humans, it is possible to skip some development tests, and since the manufacturing method of the drug has already been established, it is possible to shorten the development period and reduce R&D costs. Therefore, the drug repositioning method is one of the methods that should be tried in order to achieve the initial control of a pandemic. In Japan, it has been announced that research and development using drug repositioning has been conducted to date. The following are some of the candidates that have already been identified as COVID-19 therapeutic agents in Japan and are expected to be identified in the future.


Assuntos
COVID-19 , Preparações Farmacêuticas , Antivirais/farmacologia , Antivirais/uso terapêutico , Reposicionamento de Medicamentos , Humanos , Pandemias , SARS-CoV-2
5.
Nihon Yakurigaku Zasshi ; 157(1): 31-37, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-34980809

RESUMO

Remdesivir is a direct-acting antiviral agent that inhibits viral RNA synthesis developed by Gilead Sciences, Inc. in the United States. It has been shown to have antiviral activity against single-stranded RNA viruses, including coronaviruses, in cell culture systems and animal models, and has been developed as a therapeutic agent for Ebola virus infection since 2015. however, to date, it has not been approved in any country. A novel coronavirus infection (COVID-19) was identified in Wuhan, Hubei Province, China in Dec, 2019, and is a respiratory disease characterized by fever, cough, and dyspnea. In severe cases, it may cause serious pneumonia, multi-organ failure and death. Gilead Sciences, Inc. U.S. embarked on the development of COVID-19 as a therapeutic drug, using remdesivir, which has shown in vitro and in vivo antiviral activities against MERS-CoV and SARS-CoV, which are single-stranded RNA coronaviruses that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). The in vitro antiviral activity of remdesivir against SARS-CoV-2, which causes COVID-19, was confirmed and clinical studies were initiated in February 2020. Based on the results of clinical studies conducted by the National Institute of Allergy and Infectious Diseases (NIAID) and Gilead Sciences, Inc. and experience of administration from a compassionate use, an exceptional approval system based on the "Pharmaceuticals and Medical Devices Act" was also approved in Japan as of May 7, 2020 for the indication of "infections caused by SARS-CoV-2." In this article, the background of the development and clinical results of remdesivir are described.


Assuntos
COVID-19 , Doença pelo Vírus Ebola , Hepatite C Crônica , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Doença pelo Vírus Ebola/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , SARS-CoV-2
6.
Emerg Microbes Infect ; 11(1): 195-207, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34919035

RESUMO

Ebola virus disease (EVD) is a severe and frequently lethal disease caused by Ebola virus (EBOV). The latest occasional EVD outbreak (2013-2016) in Western African, which was accompanied by a high fatality rate, showed the great potential of epidemic and pandemic spread. Antiviral therapies against EBOV are very limited, strain-dependent (only antibody therapies are available) and mostly restricted to symptomatic treatment, illustrating the urgent need for novel antiviral strategies. Thus, we evaluated the effect of the clinically widely used antifungal itraconazole and the antidepressant fluoxetine for a repurposing against EBOV infection. While itraconazole, similar to U18666A, directly binds to and inhibits the endosomal membrane protein Niemann-Pick C1 (NPC1), fluoxetine, which belongs to the structurally unrelated group of weakly basic, amphiphile so-called "functional inhibitors of acid sphingomyelinase" (FIASMA) indirectly acts on the lysosome-residing acid sphingomyelinase via enzyme detachment leading to subsequent lysosomal degradation. Both, the drug-induced endolysosomal cholesterol accumulation and the altered endolysosomal pH, might interfere with the fusion of viral and endolysosomal membrane, preventing infection with EBOV. We further provide evidence that cholesterol imbalance is a conserved cross-species mechanism to hamper EBOV infection. Thus, exploring the endolysosomal host-pathogen interface as a suitable antiviral treatment may offer a general strategy to combat EBOV infection.


Assuntos
Antivirais/farmacologia , Colesterol/metabolismo , Ebolavirus/efeitos dos fármacos , Endossomos/metabolismo , Fluoxetina/farmacologia , Doença pelo Vírus Ebola/metabolismo , Itraconazol/farmacologia , Ebolavirus/genética , Ebolavirus/fisiologia , Endossomos/efeitos dos fármacos , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/genética , Doença pelo Vírus Ebola/virologia , Humanos , Proteína C1 de Niemann-Pick/genética , Proteína C1 de Niemann-Pick/metabolismo , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Esfingomielina Fosfodiesterase/genética , Esfingomielina Fosfodiesterase/metabolismo , Internalização do Vírus/efeitos dos fármacos
7.
J Pharm Biomed Anal ; 209: 114538, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34929567

RESUMO

The 3C-like protease (3CLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential to the virus life cycle and is supposed to be a potential target for the treatment of coronaviral infection. Traditional Chinese medicines (TCMs) have played an impressive role in the treatment of COVID-19 in China. The effectiveness of TCM formulations prompts scientists to take continuous effort on searching for bioactive small molecules from the ancient resources. Herein, we developed a native mass spectrometry-based affinity-selection method for rapid screening of active small molecules from crude herbal extracts applied for COVID-19 therapy. Six common herbs named Lonicera japonica, Scutellaria baicalensis, Forsythia suspensa, Glycyrrhiza uralensis, Cirsium japonicum, and Andrographis paniculata were investigated. After preliminary separation of the crude extracts, the fractions were incubated with 3CLpro. A native MS-based affinity screening assay was then conducted to search for the protein-ligand complexes. A UHPLC-Q/TOF-MS with UNIFI data acquisition and data processing software was applied to identify the hit compounds. Standard compounds were used to verify the outcomes. Among the 16 hits, three flavonoids, baicalein, scutellarein and ganhuangenin, were identified as potential noncovalent inhibitors against 3CLpro with IC50 values of 0.94, 3.02, and 0.84 µM, respectively. Their binding affinities were further characterized by native MS, with Kd values being 1.43, 3.85, and 1.09 µM, respectively. Overall, we established an efficient native MS-based strategy for discovering 3CLpro ligands from crude mixtures, which supplies a potential strategy of small molecule lead discovery from TCMs.


Assuntos
COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , Humanos , Simulação de Acoplamento Molecular , Peptídeo Hidrolases , Inibidores de Proteases/farmacologia
8.
J Am Soc Mass Spectrom ; 33(1): 181-188, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34939787

RESUMO

Affinity selection-mass spectrometry, which includes magnetic microbead affinity selection-screening (MagMASS), is ideal for the discovery of ligands in complex mixtures that bind to pharmacological targets. Therapeutic agents are needed to prevent or treat COVID-19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infection of human cells by SARS-CoV-2 involves binding of the virus spike protein subunit 1 (S1) to the human cell receptor angiotensin converting enzyme-2 (ACE2). Like antibodies, small molecules have the potential to block the interaction of the viral S1 protein with human ACE2 and prevent SARS-CoV-2 infection. Therefore, a MagMASS assay was developed for the discovery of ligands to the S1 protein. Unlike previous MagMASS approaches, this new assay used robotics for 5-fold enhancement of throughput and sensitivity. The assay was validated using the SBP-1 peptide, which is identical to the ACE2 amino acid sequence recognized by the S1 protein, and then applied to the discovery of natural ligands from botanical extracts. Small molecule ligands to the S1 protein were discovered in extracts of the licorice species, Glycyrrhiza inflata. In particular, the licorice ligand licochalcone A was identified through dereplication and comparison with standards using HPLC with high-resolution tandem mass spectrometry.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Descoberta de Drogas/métodos , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/química , Sítios de Ligação/efeitos dos fármacos , COVID-19/metabolismo , Chalconas/química , Chalconas/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Fabaceae/química , Humanos , Ligantes , Espectrometria de Massas/métodos , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos , SARS-CoV-2/metabolismo
9.
Vet Microbiol ; 264: 109299, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34896854

RESUMO

Porcine deltacoronavirus (PDCoV) is an emerging porcine enteric coronavirus that causes severe diarrhea in piglets and results in serious economic losses. There are no effective vaccines and antiviral drugs to prevent and treat PDCoV infection currently. Griffithsin (GRFT) is a lectin with potent antiviral activity against enveloped viruses because of its ability to specifically bind N-linked high-mannose oligosaccharides. GRFT has been reported to possess antiviral activity against severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and porcine epidemic diarrhea virus (PEDV). Here, we first confirmed the antiviral activity of GRFT against PDCoV in vitro. The infected cells (%) and virus titers were significantly decreased at concentration 1 µg/mL or above of GRFT. Time-course experiments revealed that GRFT inhibits PDCoV infection at the adsorption and penetration step. GRFT binding to PDCoV spike (S) protein on the surface wraps the virus and blocks its entry. The outstanding antiviral potency indicates that GRFT has the potential value as a candidate drug for the prevention and treatment of PDCoV infection.


Assuntos
Deltacoronavirus , Lectinas de Plantas , Animais , Antivirais/farmacologia , Técnicas de Cultura de Células/veterinária , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/veterinária , Deltacoronavirus/efeitos dos fármacos , Lectinas de Plantas/farmacologia , Suínos , Doenças dos Suínos/tratamento farmacológico
10.
Phytomedicine ; 95: 153874, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34923232

RESUMO

BACKGROUND: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human coronavirus 229E (HCoV-229E) pose a huge threat to human public health, no specific treatment is available. Jinzhen granule (JZ) is a traditional eight ingredients-Chinese medicine with prominent efficacy for treating viral-induced diseases. However, little is known about the antiviral effect and mechanism of JZ against SARS-CoV-2 and HCoV-229E. PURPOSE: This study aimed to reveal the antiviral effects of JZ against SARS-CoV-2 and HCoV-229E, and to further explore the underlying mechanisms regulating the host immune response. METHODS: The chromatographic separation of JZ was performed using a Shimadzu analytical high-performance liquid chromatograph with UV detection and Alltech ELSD 2000ES. We conducted cytopathic effect (CPE) and plaque reduction assays to evaluate the antiviral effect of JZ. A lethal human angiotensin converting enzyme 2 (hACE2) transgenic mouse model of SARS-CoV-2 was established to determine the protective effect of JZ on mortality and lung virus titers. Real-time quantitative PCR assays were used to analyze the expression of proinflammatory cytokines in vitro and in vivo. Western blotting was further performed to determine the activities on regulating the nuclear factor kappa B (NF-κB)/MAPK pathway. Finally, mitochondrial membrane potential assays, flow cytometry analysis and western blotting were used to assess the anti-apoptotic potency toward HCoV-229E infection. RESULTS: The results showed that 13 chemical components were identified and five peaks were determined and quantitated (gallic acid 1.97 mg/g, baicalin 20.69 mg/g, glycyrrhizic acid 4.92 mg/g, hyodeoxycholic acid 4.86 mg/g, cholic acid 4.07 mg/g). We found that JZ exerted inhibitory potency against SARS-CoV-2 and HCoV-229E in vitro by using CPE and plaque reduction assays, and it was further found that JZ protected mice infected by SARS-CoV-2 from death and inhibited lung virus titers. JZ also significantly decreased the induction of inflammatory cytokines (IL-1α, IL-6, CCL-5 and MIP-1ß), similar to the observed in vitro effect. Moreover, JZ suppressed the release of inflammatory cytokines in vitro and it decreased the protein expression of p-p38 MAPK, p-JNK, p-NF-κB p65 and p-IκBα induced by HCoV-229E and increased the expression of IκBα. Notably, JZ significantly protected HCoV-229E-infected Huh-7 cells from mitochondrial damage and decreased apoptotic cells. The activation of the mitochondria-mediated apoptotic pathway was inhibited by JZ, as shown by the reduced expression of cleaved caspase-9, caspase-3 and p-PARP. CONCLUSIONS: In conclusion, JZ (gallic acid 1.97 mg/g, baicalin 20.69 mg/g, glycyrrhizic acid 4.92 mg/g, hyodeoxycholic acid 4.86 mg/g, cholic acid 4.07 mg/g) exhibited antiviral activities against SARS-CoV-2 and HCoV-229E by regulating the NF-κB/MAPK pathway and the mitochondria-mediated apoptotic pathway. These findings demonstrated the efficacy of JZ against CoVs and suggested JZ treatment as a novel clinical therapeutic strategy for COVID-19.


Assuntos
COVID-19 , Coronavirus Humano 229E , Animais , Antivirais/farmacologia , Humanos , Camundongos , NF-kappa B , SARS-CoV-2
11.
J Mol Graph Model ; 110: 108050, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34655918

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing COVID-19 pandemic. With some notable exceptions, safe and effective vaccines, which are now being widely distributed globally, have largely begun to stabilise the situation. However, emerging variants of concern and vaccine hesitancy are apparent obstacles to eradication. Therefore, the need for the development of potent antivirals is still of importance. In this context, the SARS-CoV-2 main protease (Mpro) is a critical target and numerous clinical trials, predominantly in the private domain, are currently in progress. Here, our aim was to extend our previous studies, with hypericin and cyanidin-3-O-glucoside, as potential inhibitors of the SARS-CoV-2 Mpro. Firstly, we performed all-atom microsecond molecular dynamics simulations, which highlight the stability of the ligands in the Mpro active site over the duration of the trajectories. We also invoked PELE Monte Carlo simulations which indicate that both hypericin and cyanidin-3-O-glucoside preferentially interact with the Mpro active site and known allosteric sites. For further validation, we performed an in vitro enzymatic activity assay that demonstrated that hypericin and cyanidin-3-O-glucoside inhibit Mpro activity in a dose-dependent manner at biologically relevant (µM) concentrations. However, both ligands are much less potent than the well-known covalent antiviral GC376, which was used as a positive control in our experiments. Nevertheless, the biologically relevant activity of hypericin and cyanidin-3-O-glucoside is encouraging. In particular, a synthetic version of hypericin has FDA orphan drug designation, which could simplify potential clinical evaluation in the context of COVID-19.


Assuntos
COVID-19 , Pandemias , Antivirais/farmacologia , Proteases 3C de Coronavírus , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Método de Monte Carlo , Inibidores de Proteases/farmacologia , SARS-CoV-2
12.
Methods Mol Biol ; 2409: 47-61, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34709635

RESUMO

Dengue Virus (DENV) and ZIKA Virus (ZIKV) are two important human pathogens that belong to the Flavivirus genus of positive strand RNA viruses. Symptoms of DENV infections range from asymptomatic or mild fever to life-threatening forms, while ZIKV can lead to teratogenic effects such as microcephaly in newborns and neurological disease like the Guillain-Barré syndrome.Non-Structural Protein 5 (NS5) is the largest and most conserved enzyme across flaviviruses and hence constitutes a prime target for developing pan-flavivirus antiviral inhibitors. NS5 results from the gene fusion between a methyltransferase at the N-terminus of the protein and an RNA-dependent RNA polymerase (RdRp) at the C-terminal end. The NS5 protein plays key roles in replication and modification of viral RNA and its inhibition by potent antiviral drugs could prevent severe symptoms associated with infections.We have optimized purification and crystallization protocols to obtain active recombinant proteins suitable for structure-based drug discovery for both the full-length NS5 protein and the polymerase domain of NS5 from DENV and ZIKV .


Assuntos
Vírus da Dengue , Zika virus , Antivirais/farmacologia , Cristalização , Dengue , Humanos , Recém-Nascido , Proteínas não Estruturais Virais/genética , Zika virus/genética , Infecção por Zika virus
13.
Colloids Surf B Biointerfaces ; 209(Pt 1): 112172, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34715596

RESUMO

In this work, biocompatible, antimicrobial, and antiviral nanocomposites were prepared through two steps. In the first step, periodate oxidation of cellulose was performed to get dialdehyde cellulose (DAC). The second step included the reaction of DAC with sulfur-containing amino acids included Cysteine (Cys) and Methionine (Meth) in the presence of graphene oxide (GO). The prepared nanocomposites were characterized via FT-IR, SEM, TEM, and TGA. Antimicrobial and antiviral activities for all designed nanocomposites besides DAC were carried out. Both DAC/GO/Cys and DAC/GO/Meth exhibited a promising antimicrobial activity against Gram-negative (E. coli and P. aeruginosa), Gram-positive (B. subtilis and S. aureus), and unicellular fungi (C. Albicans and C. neoformans), while the DAC/GO/Cys/Meth nanocomposite was the lowest. Moreover, all designed nanocomposites have a strong antiviral activity against Herpes simplex virus 1(HSV-1) at minimum nontoxic concentration. Additionally, Computational procedures and Molecular docking showed the reactivity and stability of the molecules that have biological activity against Gram-positive, Gram-negative, and HSV-1. As well as DAC incorporation with amino acid enhanced their reactivity and their interaction.


Assuntos
Anti-Infecciosos , Grafite , Nanocompostos , Aminoácidos , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Antivirais/farmacologia , Celulose , Escherichia coli , Simulação de Acoplamento Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus
14.
J Ethnopharmacol ; 284: 114797, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-34737005

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: For millennia, Artemisia annua L. was used in Southeast Asia to treat "fever". This medicinal plant is effective against multiple pathogens and is used by many global communities as a source of artemisinin derivatives that are first-line drugs to treat malaria caused by Plasmodium parasites. AIM OF THE STUDY: The SARS-CoV-2 (Covid-19) global pandemic has killed millions and evolved numerous variants, with delta being the most transmissible to date and causing break-through infections of vaccinated individuals. We further queried the efficacy of A. annua cultivars against new variants. MATERIALS AND METHODS: Using Vero E6 cells, we measured anti-SARS-CoV-2 activity of dried-leaf hot-water A. annua L. extracts of four cultivars, A3, BUR, MED, and SAM, to determine their efficacy against five infectious variants of the virus: alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2), and kappa (B.1.617.1). RESULTS: In addition to being effective against the original wild type (WT) WA1, A. annua cultivars A3, BUR, MED, and SAM were also potent against all five variants. IC50 and IC90 values based on measured artemisinin content ranged from 0.3 to 8.4 µM and 1.4-25.0 µM, respectively. The IC50 and IC90 values based on dried leaf weight (DW) used to make the tea infusions ranged from 11.0 to 67.7 µg DW and 59.5-160.6 µg DW, respectively. Cell toxicity was insignificant at a leaf dry weight of ≤50 µg in the extract of any cultivar. CONCLUSIONS: Results suggest that oral consumption of A. annua hot-water extracts (tea infusions) could potentially provide a cost-effective therapy to help stave off the rapid global spread of these variants, buying time for broader implementation of vaccines.


Assuntos
Antivirais/farmacologia , Artemisia annua/química , COVID-19/virologia , Extratos Vegetais/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Concentração Inibidora 50 , Extratos Vegetais/química , Células Vero
15.
Eur J Med Chem ; 227: 113966, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34749200

RESUMO

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented in human history. As a major structural protein, nucleocapsid protein (NPro) is critical to the replication of SARS-CoV-2. In this work, 17 NPro-targeting phenanthridine derivatives were rationally designed and synthesized, based on the crystal structure of NPro. Most of these compounds can interact with SARS-CoV-2 NPro tightly and inhibit the replication of SARS-CoV-2 in vitro. Compounds 12 and 16 exhibited the most potent anti-viral activities with 50% effective concentration values of 3.69 and 2.18 µM, respectively. Furthermore, site-directed mutagenesis of NPro and Surface Plasmon Resonance (SPR) assays revealed that 12 and 16 target N-terminal domain (NTD) of NPro by binding to Tyr109. This work found two potent anti-SARS-CoV-2 bioactive compounds and also indicated that SARS-CoV-2 NPro-NTD can be a target for new anti-virus agents.


Assuntos
Antivirais/química , Proteínas do Nucleocapsídeo de Coronavírus/antagonistas & inibidores , Fenantridinas/química , SARS-CoV-2/metabolismo , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/virologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Desenho de Fármacos , Humanos , Cinética , Simulação de Acoplamento Molecular , Fenantridinas/metabolismo , Fenantridinas/farmacologia , Fenantridinas/uso terapêutico , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Células Vero
16.
Phytochemistry ; 193: 112984, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34757253

RESUMO

Papain-like protease (PLpro) is a key enzyme encoded by SARS-CoV-2 that is essential for viral replication and immune evasion. Significant suppression of viral spread and promotion of antiviral immunity can be achieved by inhibition of PLpro, revealing an inspiring strategy for COVID-19 treatment. This study aimed to discover PLpro inhibitors by investigating the national compound library of traditional Chinese medicines (NCLTCMs), a phytochemical library comprising over 9000 TCM-derived compounds. Through virtual screening and enzymatic evaluations, nine natural biflavones were confirmed to be effective PLpro inhibitors with IC50 values ranging from 9.5 to 43.2 µM. Pro-ISG15 cleavage assays further demonstrated that several biflavones exhibited potent inhibitory effects against PLpro-mediated deISGylation, a key process involved in viral immune evasion. Herein, we report the discovery, antiviral evaluation, structure-activity relationship elucidation and molecular docking investigation of biflavones as potent inhibitors of SARS-CoV-2 PLpro.


Assuntos
COVID-19 , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases Semelhantes à Papaína de Coronavírus , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , SARS-CoV-2
17.
J Hazard Mater ; 424(Pt A): 127391, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34879581

RESUMO

Personal protective equipment (PPE) such as face masks is vital in battling the COVID-19 crisis, but the dominant polypropylene-based PPE are lack of antiviral/antibacterial activities and environmental friendliness, and have hazardous impact on the soil and aquatic ecosystems. The work presented herein focused on developing biodegradable, antiviral, and antibacterial cellulose nonwovens (AVAB-CNWs) as a multi-functional bioprotective layer for better protection against coronavirus SARS-CoV-2 and addressing environmental concerns raised by the piling of COVID-19 related wastes. Both guanidine-based polymer and neomycin sulfate (NEO) were reactive-modified and covalently grafted onto the surface of cellulose nonwovens, thereby conferring outstanding antiviral and antibacterial activities to the nonwovens without deteriorating the microstructure and biodegradability. Through adjusting the grafting amount of active components and selecting appropriate reagents for pretreatment, the antimicrobial activity and hydrophobicity for self-cleaning of the nonwovens can be tuned. More importantly, we demonstrated for the first time that such multi-functional nonwovens are capable of inactivating SARS-CoV-2 instantly, leading to high virucidal activity (> 99.35%), which is unachievable by conventional masks used nowadays. Meanwhile, the robust breathability and biodegradability of AVAB-CNWs were well maintained. The applications of the as-prepared nonwovens as high-performance textile can be readily extended to other areas in the fight against COVID-19.


Assuntos
Antivirais , COVID-19 , Antibacterianos/farmacologia , Antivirais/farmacologia , Celulose , Ecossistema , Humanos , Microplásticos , Plásticos , SARS-CoV-2
18.
Int J Infect Dis ; 115: 171-177, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34902582

RESUMO

BACKGROUND: Hepatitis C virus (HCV) is a global public health problem. Second-generation direct-acting antivirals targeting non-structural regions on the viral genome are the cornerstone for treatment of chronic infection. However, resistance-associated variants (RAVs) have been reported to be associated with therapeutic failure. The aim of this study was to assess the frequency of variants, including RAVs, in the NS3, NS5A and NS5B regions at baseline in Brazilian patients with chronic hepatitis C with HCV genotypes 1a, 1b and 3a. METHODS: Serum samples from 13 patients were used to obtain viral RNA. Massively parallel sequencing was performed using genotype-specific amplicons and a panel of Ampliseq technology for all genotypes. RESULTS: Several non-synonymous substitutions were detected at baseline for 11 responders and pre-/post-treatment for two non-responders. HCV genotype 3a was found to have significantly more non-synonymous substitutions than HCV genotype 1 in the NS3 and NS5A regions. Analyses were conducted using quantitative and qualitative inter- and intrapatient comparisons. Variants that confer resistance to the treatment used by the patients were found in both responders and non-responders. CONCLUSIONS: A wide frequency distribution of RAVs was found at baseline, and this did not interfere with the achievement of a sustained response. Evaluation of the presence of RAVs requires additional study in order to determine clinical relevance.


Assuntos
Hepatite C Crônica , Hepatite C , Antivirais/farmacologia , Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Proteínas não Estruturais Virais/genética
19.
J Fish Dis ; 45(1): 59-68, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34536027

RESUMO

White spot syndrome virus (WSSV) is a pathogenic and threatening virus in shrimp culture for which there is no effective control strategy. Finding antiviral lead compounds for the development of anti-WSSV drugs is urgent and necessary; in this study, esculin from 12 monomeric compounds exhibited an excellent anti-WSSV activity. The results showed that esculin increased the survival rate of WSSV-infected shrimps by 59% and reduced the virus copy number in vivo over 90% at 100 µM. In the pre-treatment and post-treatment experiments, esculin could prevent and treat WSSV infection. Compared with the control group, the virus copy number decreased by 30% after 6 h of esculin pre-incubation with WSSV particles and inhibited horizontal transmission of WSSV to a certain extent. Considering that the antiviral activity of esculin was stable in the aquacultural water for 2 days, we evaluated the dosing pattern of continuous medication changes. Obviously, the survival rate of WSSV-infected shrimps was 0% at 108 h when no esculin exchange was made, while at 120 h the survival rate was over 40% at continuous medicine changes. In addition, esculin significantly increased the expression of antimicrobial peptides and thus improved the ability of shrimp to resist WSSV. Overall, our findings suggest that esculin has the potential to be developed into an anti-WSSV medicine.


Assuntos
Antivirais/farmacologia , Esculina/farmacologia , Doenças dos Peixes , Penaeidae , Vírus da Síndrome da Mancha Branca 1 , Animais , Aquicultura , Surtos de Doenças , Doenças dos Peixes/tratamento farmacológico , Doenças dos Peixes/virologia , Penaeidae/virologia , Vírus da Síndrome da Mancha Branca 1/efeitos dos fármacos
20.
Pestic Biochem Physiol ; 180: 105002, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34955185

RESUMO

TEER-decreasing protein (TDP) from Flammulina velutipes was antiviral resource against tobacco mosaic virus (TMV). However, the resistance mechanisms have not been clarified. In this study, the fTDP (fusion teer-decreasing protein), obtained by prokaryotic fusion expression system, exhibited obvious protective efficacy against TMV and significantly suppressed the reproduction of TMV in tobacco. Transcriptomics and proteomics analysis showed that fTDP may interact with a receptor, activate the mitogen-activated protein kinase (MAPK) pathway and NB-ARC and increase the content of reactive oxygen species (ROS) and salicylic acid (SA), which promoted the hypersensitive response (HR) and system acquired resistance (SAR). SAR caused increased expression of catalase (CAT), pathogenesis-related protein 1 (PR1), phenylalanine ammonia lyase (PAL) and other proteins involved in pathogen defense, such as chalcone-dihydroflavone isomerase (CHI) and cytochrome P450. In conclusion, SAR was induced by fTDP to protect tobacco from TMV infection and alleviate the symptoms caused by the virus. The study provided a theoretical basis for the application of the TDP protein, which may represent a potential biopesticide.


Assuntos
Vírus do Mosaico do Tabaco , Antivirais/farmacologia , Doenças das Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ácido Salicílico , Transdução de Sinais , Tabaco/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA