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1.
Molecules ; 25(18)2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899754

RESUMO

The emergence of the Coronavirus Disease 2019 (COVID-19) caused by the SARS-CoV-2 virus has led to an unprecedented pandemic, which demands urgent development of antiviral drugs and antibodies; as well as prophylactic approaches, namely vaccines. Algae biotechnology has much to offer in this scenario given the diversity of such organisms, which are a valuable source of antiviral and anti-inflammatory compounds that can also be used to produce vaccines and antibodies. Antivirals with possible activity against SARS-CoV-2 are summarized, based on previously reported activity against Coronaviruses or other enveloped or respiratory viruses. Moreover, the potential of algae-derived anti-inflammatory compounds to treat severe cases of COVID-19 is contemplated. The scenario of producing biopharmaceuticals in recombinant algae is presented and the cases of algae-made vaccines targeting viral diseases is highlighted as valuable references for the development of anti-SARS-CoV-2 vaccines. Successful cases in the production of functional antibodies are described. Perspectives on how specific algae species and genetic engineering techniques can be applied for the production of anti-viral compounds antibodies and vaccines against SARS-CoV-2 are provided.


Assuntos
Antivirais/farmacologia , Produtos Biológicos/farmacologia , Chlamydomonas reinhardtii/genética , Infecções por Coronavirus/tratamento farmacológico , Lectinas/farmacologia , Pneumonia Viral/tratamento farmacológico , Polifenóis/farmacologia , Polissacarídeos/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Núcleo Celular/química , Núcleo Celular/genética , Núcleo Celular/metabolismo , Chlamydomonas reinhardtii/química , Chlamydomonas reinhardtii/metabolismo , Cloroplastos/química , Cloroplastos/genética , Cloroplastos/metabolismo , Infecções por Coronavirus/prevenção & controle , Engenharia Genética/métodos , Humanos , Lectinas/química , Lectinas/isolamento & purificação , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Pandemias , Polifenóis/química , Polifenóis/isolamento & purificação , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Vacinas Virais/biossíntese , Vacinas Virais/farmacologia
2.
Molecules ; 25(17)2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32872217

RESUMO

A pandemic caused by the novel coronavirus (SARS-CoV-2 or COVID-19) began in December 2019 in Wuhan, China, and the number of newly reported cases continues to increase. More than 19.7 million cases have been reported globally and about 728,000 have died as of this writing (10 August 2020). Recently, it has been confirmed that the SARS-CoV-2 main protease (Mpro) enzyme is responsible not only for viral reproduction but also impedes host immune responses. The Mpro provides a highly favorable pharmacological target for the discovery and design of inhibitors. Currently, no specific therapies are available, and investigations into the treatment of COVID-19 are lacking. Therefore, herein, we analyzed the bioactive phytocompounds isolated by gas chromatography-mass spectroscopy (GC-MS) from Tinospora crispa as potential COVID-19 Mpro inhibitors, using molecular docking study. Our analyses unveiled that the top nine hits might serve as potential anti-SARS-CoV-2 lead molecules, with three of them exerting biological activity and warranting further optimization and drug development to combat COVID-19.


Assuntos
Antivirais/química , Betacoronavirus/química , Compostos Fitoquímicos/química , Inibidores de Proteases/química , Tinospora/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/classificação , Antivirais/isolamento & purificação , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Domínio Catalítico , Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases/química , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Descoberta de Drogas , Cromatografia Gasosa-Espectrometria de Massas , Expressão Gênica , Humanos , Cinética , Simulação de Acoplamento Molecular , Pandemias , Compostos Fitoquímicos/classificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/classificação , Inibidores de Proteases/isolamento & purificação , Inibidores de Proteases/farmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Especificidade por Substrato , Termodinâmica , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
3.
Molecules ; 25(17)2020 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-32842606

RESUMO

Presently, there are no approved drugs or vaccines to treat COVID-19, which has spread to over 200 countries and at the time of writing was responsible for over 650,000 deaths worldwide. Recent studies have shown that two human proteases, TMPRSS2 and cathepsin L, play a key role in host cell entry of SARS-CoV-2. Importantly, inhibitors of these proteases were shown to block SARS-CoV-2 infection. Here, we perform virtual screening of 14,011 phytochemicals produced by Indian medicinal plants to identify natural product inhibitors of TMPRSS2 and cathepsin L. AutoDock Vina was used to perform molecular docking of phytochemicals against TMPRSS2 and cathepsin L. Potential phytochemical inhibitors were filtered by comparing their docked binding energies with those of known inhibitors of TMPRSS2 and cathepsin L. Further, the ligand binding site residues and non-covalent interactions between protein and ligand were used as an additional filter to identify phytochemical inhibitors that either bind to or form interactions with residues important for the specificity of the target proteases. This led to the identification of 96 inhibitors of TMPRSS2 and 9 inhibitors of cathepsin L among phytochemicals of Indian medicinal plants. Further, we have performed molecular dynamics (MD) simulations to analyze the stability of the protein-ligand complexes for the three top inhibitors of TMPRSS2 namely, qingdainone, edgeworoside C and adlumidine, and of cathepsin L namely, ararobinol, (+)-oxoturkiyenine and 3α,17α-cinchophylline. Interestingly, several herbal sources of identified phytochemical inhibitors have antiviral or anti-inflammatory use in traditional medicine. Further in vitro and in vivo testing is needed before clinical trials of the promising phytochemical inhibitors identified here.


Assuntos
Antivirais/química , Betacoronavirus/efeitos dos fármacos , Catepsina L/química , Compostos Fitoquímicos/química , Inibidores de Proteases/química , Receptores Virais/química , Serina Endopeptidases/química , Sequência de Aminoácidos , Antivirais/isolamento & purificação , Antivirais/farmacologia , Betacoronavirus/patogenicidade , Sítios de Ligação , Catepsina L/antagonistas & inibidores , Catepsina L/genética , Catepsina L/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Cumarínicos/química , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Expressão Gênica , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Índia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Monossacarídeos/química , Monossacarídeos/isolamento & purificação , Monossacarídeos/farmacologia , Pandemias , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Inibidores de Proteases/isolamento & purificação , Inibidores de Proteases/farmacologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Quinazolinas/química , Quinazolinas/isolamento & purificação , Quinazolinas/farmacologia , Receptores Virais/antagonistas & inibidores , Receptores Virais/genética , Receptores Virais/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Termodinâmica , Internalização do Vírus/efeitos dos fármacos
4.
Theranostics ; 10(17): 7821-7835, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32685022

RESUMO

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently become a pandemic. As the sudden emergence and rapid spread of SARS-CoV-2 is endangering global health and the economy, the development of strategies to contain the virus's spread are urgently needed. At present, various diagnostic kits to test for SARS-CoV-2 are available for use to initiate appropriate treatment faster and to limit further spread of the virus. Several drugs have demonstrated in vitro activity against SARS-CoV-2 or potential clinical benefits. In addition, institutions and companies worldwide are working tirelessly to develop treatments and vaccines against COVID-19. However, no drug or vaccine has yet been specifically approved for COVID-19. Given the urgency of the outbreak, we focus here on recent advances in the diagnostics, treatment, and vaccine development for SARS-CoV-2 infection, helping to guide strategies to address the current COVID-19 pandemic.


Assuntos
Betacoronavirus , Técnicas de Laboratório Clínico , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Vacinas Virais , Antivirais/isolamento & purificação , Antivirais/uso terapêutico , Betacoronavirus/genética , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , Técnicas de Laboratório Clínico/tendências , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Desenvolvimento de Medicamentos/tendências , Humanos , Imunização Passiva/tendências , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/prevenção & controle , Pneumonia Viral/terapia , Nanomedicina Teranóstica/tendências , Vacinas Virais/isolamento & purificação , Vacinas Virais/farmacologia
5.
Theranostics ; 10(16): 7034-7052, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32641977

RESUMO

This review provides an update for the international research community on the cell modeling tools that could accelerate the understanding of SARS-CoV-2 infection mechanisms and could thus speed up the development of vaccines and therapeutic agents against COVID-19. Many bioengineering groups are actively developing frontier tools that are capable of providing realistic three-dimensional (3D) models for biological research, including cell culture scaffolds, microfluidic chambers for the culture of tissue equivalents and organoids, and implantable windows for intravital imaging. Here, we review the most innovative study models based on these bioengineering tools in the context of virology and vaccinology. To make it easier for scientists working on SARS-CoV-2 to identify and apply specific tools, we discuss how they could accelerate the discovery and preclinical development of antiviral drugs and vaccines, compared to conventional models.


Assuntos
Antivirais/isolamento & purificação , Antivirais/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/prevenção & controle , Vacinas Virais/isolamento & purificação , Vacinas Virais/farmacologia , Betacoronavirus/química , Betacoronavirus/genética , Betacoronavirus/imunologia , Bioengenharia/métodos , Bioengenharia/tendências , Reatores Biológicos , Técnicas de Cultura de Células , Simulação por Computador , Infecções por Coronavirus/imunologia , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Avaliação de Medicamentos/métodos , Avaliação de Medicamentos/tendências , Farmacorresistência Viral , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Modelos Biológicos , Organoides/citologia , Organoides/virologia , Pneumonia Viral/imunologia , Nanomedicina Teranóstica
6.
ACS Chem Neurosci ; 11(13): 1863-1864, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32525650

RESUMO

SARS-CoV-2 remains a significant burden on human health. Several lines of evidence suggest that surveillance of sewage and waste can provide an early warning sign for COVID-19 recurrence in a community. In support, SARS-CoV-2 traces were found in sewage in several countries. With this in mind, it is notable that pests, such as cockroaches, are exposed to pathogenic microbes routinely, yet thrive in polluted environments. Such species have likely developed mechanisms to protect themselves against pathogens. In support, recent studies showed that cockroaches possess potent antibacterial molecules to shield themselves from pathogenic bacteria. Among hundreds of molecules, some contained thiazine groups, imidazoles, chromene derivatives, isoquinoline group, sulfonamides, pyrrole-containing analogs, flavanones, and furanones. Here, we propose that cockroaches are a potential source of antiviral molecules to thwart infections. Because this is an unexploited resource for potential antivirals, we believe that cockroaches offer a unique source for novel bioactive molecule(s) to counter COVID-19 with huge clinical impact worldwide.


Assuntos
Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Fatores Biológicos/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/isolamento & purificação , Betacoronavirus/fisiologia , Fatores Biológicos/isolamento & purificação , Baratas , Infecções por Coronavirus/patologia , Humanos , Pandemias , Pneumonia Viral/patologia
7.
Mar Drugs ; 18(4)2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32344720

RESUMO

Monostroma nitidum is a green single-cell layered algae that grows on the southwest coast of Japan. It is often used for salad ingredients, boiled tsukudani, soups, etc., due to its health benefits. M. nitidum is composed of many cell aggregates, and the various substances that fill the intercellular space are dietary fibers, vitamins, and minerals. Rhamnan sulfate (RS), a sulfated polysaccharide, is main the component of the fiber extracted from M. nitidum. Recently, some biological properties of RS have been demonstrated by in vitro and in vivo studies that probably protect human subjects from viruses and ameliorate vascular dysfunction caused by metabolic disorders, especially lifestyle-related diseases. In this review, we focus on the antithrombotic effects of RS and introduce its antiviral and other biological activities.


Assuntos
Clorófitas/química , Desoxiaçúcares/farmacologia , Mananas/farmacologia , Animais , Antivirais/isolamento & purificação , Antivirais/farmacologia , Desoxiaçúcares/isolamento & purificação , Fibrinolíticos/isolamento & purificação , Fibrinolíticos/farmacologia , Humanos , Japão , Mananas/isolamento & purificação , Sulfatos
8.
Mar Drugs ; 18(4)2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32331442

RESUMO

The enzymatic depolymerization of fucoidans from brown algae allowed the production of their standardized derivatives with different biological activities. This work aimed to compare the antiviral activities of native (FeF) and modified with enzyme (FeHMP) fucoidans from F. evanescens. The cytotoxicity and antiviral activities of the FeF and FeHMP against herpes viruses (HSV-1, HSV-2), enterovirus (ECHO-1), and human immunodeficiency virus (HIV-1) in Vero and human MT-4 cell lines were examined by methylthiazolyltetrazolium bromide (MTT) and cytopathic effect (CPE) reduction assays, respectively. The efficacy of fucoidans in vivo was evaluated in the outbred mice model of vaginitis caused by HSV-2. We have shown that both FeF and FeHMP significantly inhibited virus-induced CPE in vitro and were more effective against HSV. FeF exhibited antiviral activity against HSV-2 with a selective index (SI) > 40, and FeHMP with SI ˃ 20, when they were added before virus infection or at the early stages of the HSV-2 lifecycle. Furthermore, in vivo studies showed that after intraperitoneal administration (10 mg/kg), both FeF and FeHMP protected mice from lethal intravaginal HSV-2 infection to approximately the same degree (44-56%). Thus, FeF and FeHMP have comparable potency against several DNA and RNA viruses, allowing us to consider the studied fucoidans as promising broad-spectrum antivirals.


Assuntos
Antivirais/farmacologia , Fucus/química , Polissacarídeos/farmacologia , Vírus/efeitos dos fármacos , Animais , Antivirais/isolamento & purificação , Chlorocebus aethiops , Vírus de DNA/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Polissacarídeos/isolamento & purificação , Vírus de RNA/efeitos dos fármacos , Vaginite/tratamento farmacológico , Vaginite/virologia , Células Vero
9.
Biomolecules ; 10(3)2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32120929

RESUMO

Strobilanthes cusia (Nees) Kuntze is a Chinese herbal medicine used in the treatment of respiratory virus infections. The methanol extract of S. cusia leaf contains chemical components such as ß-sitosterol, indirubin, tryptanthrin, betulin, indigodole A, and indigodole B that have diverse biological activities. However, the antiviral action of S. cusia leaf and its components against human coronavirus remains to be elucidated. Human coronavirus NL63 infection is frequent among immunocompromised individuals, young children, and in the elderly. This study investigated the anti-Human coronavirus NL63 (HCoV-NL63) activity of the methanol extract of S. cusia leaf and its major components. The methanol extract of S. cusia leaf effectively inhibited the cytopathic effect (CPE) and virus yield (IC50 = 0.64 µg/mL) in HCoV-NL63-infected cells. Moreover, this extract potently inhibited the HCoV-NL63 infection in a concentration-dependent manner. Among the six components identified in the methanol extract of S. cusia leaf, tryptanthrin and indigodole B (5aR-ethyltryptanthrin) exhibited potent antiviral activity in reducing the CPE and progeny virus production. The IC50 values against virus yield were 1.52 µM and 2.60 µM for tryptanthrin and indigodole B, respectively. Different modes of time-of-addition/removal assay indicated that tryptanthrin prevented the early and late stages of HCoV-NL63 replication, particularly by blocking viral RNA genome synthesis and papain-like protease 2 activity. Notably, tryptanthrin (IC50 = 0.06 µM) and indigodole B (IC50 = 2.09 µM) exhibited strong virucidal activity as well. This study identified tryptanthrin as the key active component of S. cusia leaf methanol extract that acted against HCoV-NL63 in a cell-type independent manner. The results specify that tryptanthrin possesses antiviral potential against HCoV-NL63 infection.


Assuntos
Acanthaceae/química , Antivirais/farmacologia , Coronavirus Humano NL63/fisiologia , Quinazolinas/farmacologia , Internalização do Vírus/efeitos dos fármacos , Acanthaceae/metabolismo , Animais , Antivirais/química , Antivirais/isolamento & purificação , Antivirais/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Coronavirus Humano NL63/isolamento & purificação , Humanos , Macaca mulatta , Medicina Tradicional Chinesa , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Folhas de Planta/metabolismo , Quinazolinas/química , Quinazolinas/isolamento & purificação , Quinazolinas/uso terapêutico
10.
Viruses ; 12(3)2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32204464

RESUMO

Cats are becoming more popular as household companions and pets, forming close relationships with humans. Although feline viral diseases can pose serious health hazards to pet cats, commercialized preventative vaccines are lacking. Interferons (IFNs), especially type I IFNs (IFN-α, IFN-ß, and interferon omega (IFN-ω)), have been explored as effective therapeutic drugs against viral diseases in cats. Nevertheless, there is limited knowledge regarding feline IFN-ω (feIFN-ω), compared to IFN-α and IFN-ß. In this study, we cloned the genes encoding feIFN-ωa and feIFN-ωb from cat spleen lymphocytes. Homology and phylogenetic tree analysis revealed that these two genes belonged to new subtypes of feIFN-ω. The recombinant feIFN-ωa and feIFN-ωb proteins were expressed in their soluble forms in Escherichia coli, followed by purification. Both proteins exhibited effective anti-vesicular stomatitis virus (VSV) activity in Vero, F81 (feline kidney cell), Madin-Darby bovine kidney (MDBK), Madin-Darby canine kidney (MDCK), and porcine kidney (PK-15) cells, showing broader cross-species antiviral activity than the INTERCAT IFN antiviral drug. Furthermore, the recombinant feIFN-ωa and feIFN-ωb proteins demonstrated antiviral activity against VSV, feline coronavirus (FCoV), canine parvovirus (CPV), bovine viral diarrhea virus (BVDV), and porcine epidemic diarrhea virus (PEDV), indicating better broad-spectrum antiviral activity than the INTERCAT IFN. The two novel feIFN-ω proteins (feIFN-ωa and feIFN-ωb) described in this study show promising potential to serve as effective therapeutic agents for treating viral infections in pet cats.


Assuntos
Antivirais/farmacologia , Interferon Tipo I/genética , Interferon Tipo I/farmacologia , Sequência de Aminoácidos , Animais , Antivirais/isolamento & purificação , Sequência de Bases , Gatos , Bovinos , Linhagem Celular , Chlorocebus aethiops , Clonagem Molecular , Cães , Escherichia coli/genética , Escherichia coli/metabolismo , Interferon Tipo I/química , Interferon Tipo I/metabolismo , Filogenia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Suínos , Células Vero , Vírus/classificação , Vírus/efeitos dos fármacos
12.
mBio ; 11(1)2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047132

RESUMO

The receptor binding protein of parainfluenza virus, hemagglutinin-neuraminidase (HN), is responsible for actively triggering the viral fusion protein (F) to undergo a conformational change leading to insertion into the target cell and fusion of the virus with the target cell membrane. For proper viral entry to occur, this process must occur when HN is engaged with host cell receptors at the cell surface. It is possible to interfere with this process through premature activation of the F protein, distant from the target cell receptor. Conformational changes in the F protein and adoption of the postfusion form of the protein prior to receptor engagement of HN at the host cell membrane inactivate the virus. We previously identified small molecules that interact with HN and induce it to activate F in an untimely fashion, validating a new antiviral strategy. To obtain highly active pretriggering candidate molecules we carried out a virtual modeling screen for molecules that interact with sialic acid binding site II on HN, which we propose to be the site responsible for activating F. To directly assess the mechanism of action of one such highly effective new premature activating compound, PAC-3066, we use cryo-electron tomography on authentic intact viral particles for the first time to examine the effects of PAC-3066 treatment on the conformation of the viral F protein. We present the first direct observation of the conformational rearrangement induced in the viral F protein.IMPORTANCE Paramyxoviruses, including human parainfluenza virus type 3, are internalized into host cells by fusion between viral and target cell membranes. The receptor binding protein, hemagglutinin-neuraminidase (HN), upon binding to its cell receptor, triggers conformational changes in the fusion protein (F). This action of HN activates F to reach its fusion-competent state. Using small molecules that interact with HN, we can induce the premature activation of F and inactivate the virus. To obtain highly active pretriggering compounds, we carried out a virtual modeling screen for molecules that interact with a sialic acid binding site on HN that we propose to be the site involved in activating F. We use cryo-electron tomography of authentic intact viral particles for the first time to directly assess the mechanism of action of this treatment on the conformation of the viral F protein and present the first direct observation of the induced conformational rearrangement in the viral F protein.


Assuntos
Antivirais/farmacologia , Proteína HN/metabolismo , Vírus da Parainfluenza 3 Humana/efeitos dos fármacos , Proteínas Virais de Fusão/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos , Antivirais/isolamento & purificação , Técnicas de Cultura de Células , Linhagem Celular , Descoberta de Drogas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Proteína HN/genética , Ensaios de Triagem em Larga Escala , Humanos , Simulação de Acoplamento Molecular , Vírus da Parainfluenza 3 Humana/fisiologia , Infecções por Paramyxoviridae/tratamento farmacológico , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas Virais de Fusão/metabolismo
13.
Phytochemistry ; 171: 112229, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31901474

RESUMO

Seven undescribed cycloartane triterpenoids, pseudolarnoids A-G, together with ten known ones, were isolated from the seeds of Pseudolarix amabilis (J. Nelson) Rehder. Their structures were elucidated on the basis of spectroscopic analysis, X-ray crystallography, and ECD data. Pseudolarnoids A-C are cycloartane triterpenoids with a unique 16S, 23R-spirolactone moiety. Pseudolarnoids F, G, and pseudolarolide C demonstrated potent antiviral effects on HSV-1 in vitro.


Assuntos
Antivirais/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Triterpenos/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Cristalografia por Raios X , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Pinaceae/química , Triterpenos/química , Triterpenos/isolamento & purificação
14.
Arch Physiol Biochem ; 126(2): 116-128, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30269604

RESUMO

Chronic hepatitis C virus (HCV) infection is a significant public health problem, with a worldwide prevalence of approximately 170 million. Current therapy for HCV infection includes the prolonged administration of a combination of ribavirin and PEGylated interferon-α, for over a decade. This regimen is expensive and often associated with a poor antiviral response and unwanted side effects. A highly effective combination treatment is likely required for the future management of HCV infections and entry inhibitors could play an important role. Currently, no entry inhibitor has been licensed for the prophylactic treatment of hepatitis C. Therefore, additional agents that combat HCV infection are urgently needed and must be developed. Many phytochemical constituents have been identified that display considerable inhibition of HCV at some stage of the life cycle. This review will summarise the current state of knowledge on natural products and their possible activities in the context of HCV infection.


Assuntos
Antivirais/uso terapêutico , Produtos Biológicos/uso terapêutico , Flavonoides/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Antivirais/química , Antivirais/isolamento & purificação , Organismos Aquáticos/química , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Ensaios Clínicos como Assunto , Quimioterapia Combinada , Flavonoides/isolamento & purificação , Hepacivirus/genética , Hepacivirus/crescimento & desenvolvimento , Hepacivirus/metabolismo , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/uso terapêutico , Extratos Vegetais/química , Ribavirina/uso terapêutico
15.
Biochem Biophys Res Commun ; 523(1): 183-189, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-31843192

RESUMO

Canarium album (Lour.) Raeusch (C. album) as a normally medicinal and edible plant has been used widely in Asian countries and is considered a source of phytochemicals that are beneficial to human health. Here, we showed at the first time isocorilagin, a polyphenolic compound isolated from C. album, displayed antiviral activity against diverse strains of influenza A virus (IAV), including A/Puerto Rico/8/34 (H1N1), A/Aichi/2/68 (H3N2) and NA-H274Y (H1N1) with IC50 value of 9.19 ±â€¯1.99, 23.72 ±â€¯2.51 and 4.64 ±â€¯3.01 µM, respectively. Further mechanistic studies revealed that it clearly inhibited neuraminidase activity of IAV and directly influenced the virus release. The molecular docking studies presented isocorilagin could bind to the highly conserved residues in the active sites of NA, implying that isocorilagin may be effective against various influenza strains and not susceptible to produce drug resistance. Taken together, the results strongly suggest that isocorilagin has potential to be an effective, safe and affordable neuraminidase inhibitor against a diverse panel of IAV strains. More importantly, our work expands the biological activities of C. album extracts and provide a new option for the development of anti-influenza drug.


Assuntos
Antivirais/farmacologia , Burseraceae/química , Inibidores Enzimáticos/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Taninos/farmacologia , Animais , Antivirais/química , Antivirais/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/virologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuraminidase/metabolismo , Relação Estrutura-Atividade , Taninos/química , Taninos/isolamento & purificação
16.
J Pharm Biomed Anal ; 177: 112844, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491659

RESUMO

Traditionally, for a liquid chromatography tandem mass spectrometry (LC-MS/MS) bioanalytical assay, an external calibration curve is required to achieve accurate quantitation of an analyte. Recently, a novel in-sample calibration curves (ISCC) methodology that can achieve quick and accurate LC-MS/MS bioanalysis without the use of an external calibration curve was reported. The ISCC methodology utilizes the presence of multiple naturally occurring isotopologues of a stable isotopically labeled analyte to construct an in-sample calibration curve for the quantification. This methodology has great potential in many applications, for example biomarker measurement, quantitative proteomics and clinical diagnosis. Here, we assessed the feasibility of applying this ISCC-LC-MS/MS methodology in regulated bioanalysis using BMS-984478, a drug candidate, as the model compound. We also proposed method validation procedures/processes for this new approach for industry peers' consideration and feedback. A LC-MS/MS method using the ISCC strategy was successfully developed and validated for the quantitative analysis of BMS-984478 in human plasma over the range of 1.33-993.42 ng/mL. The validated ISCC-LC-MS/MS method was compared with a previously validated method using the conventional external calibration curve approach, and the two methods showed equivalent performance. Critical considerations and practical approaches in method development, validation and sample analysis were also discussed. Our work demonstrated that the ISCC-LC-MS/MS methodology is a promising approach for regulated LC-MS/MS bioanalysis. ISCC-LC-MS/MS methodology has its unique advantages and has great potential to be widely applied for various quantitative applications, and may even change the landscape of quantitative analysis.


Assuntos
Antivirais/isolamento & purificação , Fracionamento Químico/métodos , Espectrometria de Massas em Tandem/métodos , Antivirais/administração & dosagem , Antivirais/sangue , Calibragem , Cromatografia Líquida/métodos , Estudos de Viabilidade , Humanos , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas por Ionização por Electrospray/normas , Espectrometria de Massas em Tandem/normas
17.
Virol J ; 16(1): 150, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791359

RESUMO

BACKGROUND: Commercially available antiviral drugs, when used in the treatment of viral infections, do not always result in success. This is an urgent problem currently that needs to be addressed because several viruses including influenza and paramyxoviruses are acquiring multi-drug resistance. A potential solution for this emerging issue is to create new antiviral drugs from available compounds of natural products. It is known that the majority of drugs have been developed using compounds derived from actinomycetes, which are naturally occurring gram-positive bacteria. The purpose of this study was to investigate the antiviral properties of extremophilic actinomycetes extracts from strains that were isolated from extreme environments in Kazakhstan. METHODS: Five strains of extremophilic actinomycetes isolated from the unique ecosystems of Kazakhstan were extracted and tested for antiviral activity against influenza viruses (strains H7N1, H5N3, H1N1 and H3N2) and paramyxoviruses (Sendai Virus and Newcastle Disease Virus). The antiviral activity of these selected extracts was tested by checking their effect on hemagglutination and neuraminidase activities of the studied viruses. Additionally, actinomycetes extracts were compared with commercially available antiviral drugs and some plant preparations that have been shown to exhibit antiviral properties. RESULTS: The main findings show that extracts from strains K-192, K-340, K-362, K-522 and K525 showed antiviral activities when tested using influenza viruses, Sendai Virus, and Newcastle Disease Virus. These activities were comparable to those shown by Rimantadine and Tamiflu drugs, and "Virospan" and "Flavovir" plant preparations. CONCLUSIONS: We identified several extracts with antiviral activities against several strains of influenza viruses and paramyxoviruses. Our research findings can be applied towards characterization and development of new antiviral drugs from the active actinomycetes extracts.


Assuntos
Actinobacteria/química , Antivirais/farmacologia , Produtos Biológicos/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Actinobacteria/isolamento & purificação , Animais , Antivirais/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Misturas Complexas/isolamento & purificação , Misturas Complexas/farmacologia , Hemaglutinação , Cazaquistão , Testes de Sensibilidade Microbiana , Neuraminidase/análise , Vírus da Doença de Newcastle/efeitos dos fármacos , Vírus Sendai/efeitos dos fármacos
18.
PLoS Negl Trop Dis ; 13(12): e0007419, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31830030

RESUMO

Despite Nipah virus outbreaks having high mortality rates (>70% in Southeast Asia), there are no licensed drugs against it. In this study, we have considered all 9 Nipah proteins as potential therapeutic targets and computationally identified 4 putative peptide inhibitors (against G, F and M proteins) and 146 small molecule inhibitors (against F, G, M, N, and P proteins). The computations include extensive homology/ab initio modeling, peptide design and small molecule docking. An important contribution of this study is the increased structural characterization of Nipah proteins by approximately 90% of what is deposited in the PDB. In addition, we have carried out molecular dynamics simulations on all the designed protein-peptide complexes and on 13 of the top shortlisted small molecule ligands to check for stability and to estimate binding strengths. Details, including atomic coordinates of all the proteins and their ligand bound complexes, can be accessed at http://cospi.iiserpune.ac.in/Nipah. Our strategy was to tackle the development of therapeutics on a proteome wide scale and the lead compounds identified could be attractive starting points for drug development. To counter the threat of drug resistance, we have analysed the sequences of the viral strains from different outbreaks, to check whether they would be sensitive to the binding of the proposed inhibitors.


Assuntos
Antivirais/isolamento & purificação , Antivirais/farmacologia , Vírus Nipah/efeitos dos fármacos , Proteínas Virais/antagonistas & inibidores , Antivirais/química , Antivirais/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Proteínas Virais/química
19.
Curr Top Med Chem ; 19(31): 2868-2918, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31724505

RESUMO

Actinomycetes is an abundant resource for discovering a large number of lead compounds, which play an important role in microbial drug discovery. Compared to terrestrial microorganisms, marine actinomycetes have unique metabolic pathways because of their special living environment, which has the potential to produce a variety of bioactive substances. In this paper, secondary metabolites isolated from marine actinomycetes are reviewed (2013-2018), most of which exhibited cytotoxic, antibacterial, and antiviral biological activities.


Assuntos
Actinobacteria/química , Antibacterianos/metabolismo , Antineoplásicos/metabolismo , Antivirais/metabolismo , Produtos Biológicos/metabolismo , Actinobacteria/metabolismo , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antivirais/química , Antivirais/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Humanos
20.
PLoS Negl Trop Dis ; 13(11): e0007894, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31738758

RESUMO

Dengue is a mosquito-borne viral infection that has spread globally in recent years. Around half of the world's population, especially in the tropics and subtropics, is at risk of infection. Every year, 50-100 million clinical cases are reported, and more than 500,000 patients develop the symptoms of severe dengue infection: dengue haemorrhagic fever and dengue shock syndrome, which threaten life in Asia and Latin America. No antiviral drug for dengue is available. The dengue virus (DENV) non-structural protein 5 (NS5), which possesses the RNA-dependent RNA polymerase (RdRp) activity and is responsible for viral replication and transcription, is an attractive target for anti-dengue drug development. In the present study, 16,240 small-molecule compounds in a fragment library were screened for their capabilities to inhibit the DENV type 2 (DENV2) RdRp activities in vitro. Based on in cellulo antiviral and cytotoxity assays, we selected the compound RK-0404678 with the EC50 value of 6.0 µM for DENV2. Crystallographic analyses revealed two unique binding sites for RK-0404678 within the RdRp, which are conserved in flavivirus NS5 proteins. No resistant viruses emerged after nine rounds of serial passage of DENV2 in the presence of RK-0404678, suggesting the high genetic barrier of this compound to the emergence of a resistant virus. Collectively, RK-0404678 and its binding sites provide a new framework for antiviral drug development.


Assuntos
Antivirais/isolamento & purificação , Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , RNA Replicase/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Testes de Sensibilidade Microbiana , Ligação Proteica , RNA Replicase/química , RNA Replicase/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
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