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1.
Sci Rep ; 10(1): 16200, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004837

RESUMO

The current coronavirus (COVID-19) pandemic is exacerbated by the absence of effective therapeutic agents. Notably, patients with COVID-19 and comorbidities such as hypertension and cardiac diseases have a higher mortality rate. An efficient strategy in response to this issue is repurposing drugs with antiviral activity for therapeutic effect. Digoxin (DIG) and ouabain (OUA) are FDA drugs for heart diseases that have antiviral activity against several coronaviruses. Thus, we aimed to assess antiviral activity of DIG and OUA against SARS-CoV-2 infection. The half-maximal inhibitory concentrations (IC50) of DIG and OUA were determined at a nanomolar concentration. Progeny virus titers of single-dose treatment of DIG, OUA and remdesivir were approximately 103-, 104- and 103-fold lower (> 99% inhibition), respectively, than that of non-treated control or chloroquine at 48 h post-infection (hpi). Furthermore, therapeutic treatment with DIG and OUA inhibited over 99% of SARS-CoV-2 replication, leading to viral inhibition at the post entry stage of the viral life cycle. Collectively, these results suggest that DIG and OUA may be an alternative treatment for COVID-19, with potential additional therapeutic effects for patients with cardiovascular disease.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Digoxina/farmacologia , Ouabaína/farmacologia , Replicação Viral , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Betacoronavirus/fisiologia , Chlorocebus aethiops , Cloroquina/farmacologia , Concentração Inibidora 50 , Células Vero
2.
Int J Med Sci ; 17(16): 2511-2530, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029094

RESUMO

ShuFeng JieDu capsule (SFJDC), a traditional Chinese medicine, has been recommended for the treatment of COVID-19 infections. However, the pharmacological mechanism of SFJDC still remains vague to date. The active ingredients and their target genes of SFJDC were collected from TCMSP. COVID-19 is a type of Novel Coronavirus Pneumonia (NCP). NCP-related target genes were collected from GeneCards database. The ingredients-targets network of SFJDC and PPI networks were constructed. The candidate genes were screened by Venn diagram package for enrichment analysis. The gene-pathway network was structured to obtain key target genes. In total, 124 active ingredients, 120 target genes of SFJDC and 251 NCP-related target genes were collected. The functional annotations cluster 1 of 23 candidate genes (CGs) were related to lung and Virus infection. RELA, MAPK1, MAPK14, CASP3, CASP8 and IL6 were the key target genes. The results suggested that SFJDC cloud be treated COVID-19 by multi-compounds and multi-pathways, and this study showed that the mechanism of traditional Chinese medicine (TCM) in the treatment of disease from the overall perspective.


Assuntos
Antivirais/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Pneumonia Viral/tratamento farmacológico , Mapas de Interação de Proteínas/efeitos dos fármacos , Antivirais/química , Cápsulas/farmacologia , Caspase 3/genética , Caspase 8/genética , Infecções por Coronavirus/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Pandemias , Pneumonia Viral/genética , Mapas de Interação de Proteínas/genética , Fator de Transcrição RelA/genética
3.
Biomed Res Int ; 2020: 5324560, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029513

RESUMO

The ongoing global pandemic caused by the human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions of people and claimed hundreds of thousands of lives. The absence of approved therapeutics to combat this disease threatens the health of all persons on earth and could cause catastrophic damage to society. New drugs are therefore urgently required to bring relief to people everywhere. In addition to repurposing existing drugs, natural products provide an interesting alternative due to their widespread use in all cultures of the world. In this study, alkaloids from Cryptolepis sanguinolenta have been investigated for their ability to inhibit two of the main proteins in SARS-CoV-2, the main protease and the RNA-dependent RNA polymerase, using in silico methods. Molecular docking was used to assess binding potential of the alkaloids to the viral proteins whereas molecular dynamics was used to evaluate stability of the binding event. The results of the study indicate that all 13 alkaloids bind strongly to the main protease and RNA-dependent RNA polymerase with binding energies ranging from -6.7 to -10.6 kcal/mol. In particular, cryptomisrine, cryptospirolepine, cryptoquindoline, and biscryptolepine exhibited very strong inhibitory potential towards both proteins. Results from the molecular dynamics study revealed that a stable protein-ligand complex is formed upon binding. Alkaloids from Cryptolepis sanguinolenta therefore represent a promising class of compounds that could serve as lead compounds in the search for a cure for the corona virus disease.


Assuntos
Alcaloides/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Cryptolepis/química , Pneumonia Viral/tratamento farmacológico , Proteínas Virais/antagonistas & inibidores , Alcaloides/química , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/enzimologia , Simulação por Computador , Infecções por Coronavirus/virologia , Cisteína Endopeptidases , Avaliação Pré-Clínica de Medicamentos , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/virologia , Relação Quantitativa Estrutura-Atividade , Quinolinas/química , Quinolinas/farmacologia , RNA Replicase/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores
4.
Signal Transduct Target Ther ; 5(1): 218, 2020 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-33011739

Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Glicosídeos Cardíacos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Animais , Antivirais/química , Betacoronavirus/patogenicidade , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Bufanolídeos/química , Bufanolídeos/farmacologia , Glicosídeos Cardíacos/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cloroquina/química , Cloroquina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Digoxina/química , Digoxina/farmacologia , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno/genética , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Pandemias , Fenantrenos/química , Fenantrenos/farmacologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
5.
Signal Transduct Target Ther ; 5(1): 220, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024075
6.
Nat Commun ; 11(1): 4938, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009401

RESUMO

Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Fumarato de Dimetilo/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia Viral/tratamento farmacológico , Succinatos/agonistas , Adulto , Antioxidantes/farmacologia , Betacoronavirus/metabolismo , Infecções por Coronavirus/virologia , Fumarato de Dimetilo/farmacologia , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Interferon Tipo I , Pulmão/patologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Pandemias , Pneumonia Viral/virologia , Transdução de Sinais/efeitos dos fármacos , Succinatos/farmacologia , Replicação Viral/efeitos dos fármacos
7.
Sci Adv ; 6(35): eaba7910, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32923629

RESUMO

Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here, we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, N-(p-amylcinnamoyl)anthranilic acid (ACA), was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAVs), Zika virus (ZIKV), human immunodeficiency virus, and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion, or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein and diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral target.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Antivirais/farmacologia , Cinamatos/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , ortoaminobenzoatos/farmacologia , Células A549 , Animais , Betacoronavirus/efeitos dos fármacos , Sítios de Ligação/genética , Linhagem Celular Tumoral , Chlorocebus aethiops , Infecções por Coronavirus/patologia , Cães , Células HEK293 , Infecções por HIV/patologia , HIV-1/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/patologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Pandemias , Pneumonia Viral/patologia , Ligação Proteica/genética , Transporte Proteico/efeitos dos fármacos , RNA Viral/genética , Receptor de Interferon alfa e beta/genética , Fator de Crescimento Transformador beta1/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Infecção por Zika virus/patologia
8.
Cells ; 9(9)2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32942671

RESUMO

The small molecule macrocyclic lactone ivermectin, approved by the US Food and Drug Administration for parasitic infections, has received renewed attention in the last eight years due to its apparent exciting potential as an antiviral. It was identified in a high-throughput chemical screen as inhibiting recognition of the nuclear localizing Human Immunodeficiency Virus-1 (HIV-1) integrase protein by the host heterodimeric importin (IMP) α/ß1 complex, and has since been shown to bind directly to IMPα to induce conformational changes that prevent its normal function in mediating nuclear import of key viral and host proteins. Excitingly, cell culture experiments show robust antiviral action towards HIV-1, dengue virus (DENV), Zika virus, West Nile virus, Venezuelan equine encephalitis virus, Chikungunya virus, Pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19). Phase III human clinical trials have been completed for DENV, with >50 trials currently in progress worldwide for SARS-CoV-2. This mini-review discusses the case for ivermectin as a host-directed broad-spectrum antiviral agent for a range of viruses, including SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , HIV-1/efeitos dos fármacos , Ivermectina/farmacologia , Pneumonia Viral/tratamento farmacológico , Animais , Linhagem Celular , Chlorocebus aethiops , Dengue/tratamento farmacológico , Vírus da Dengue/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Integrase de HIV/efeitos dos fármacos , Inibidores de Integrase de HIV/farmacologia , Humanos , Pandemias , Células Vero , Zika virus/efeitos dos fármacos , Infecção por Zika virus/tratamento farmacológico
9.
Eur Rev Med Pharmacol Sci ; 24(17): 9182-9187, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32965012

RESUMO

COVID-19 pandemic has underlined that unknown viral infections, which jump from animals to humans, can be extremely dangerous. In case of new viruses as SARS-CoV2, available drugs can fail to contrast the virus aggressiveness leading patients to death. Long time is necessary to create a vaccine, but immediate solutions are necessary to stop the mortality COVID-19 related. We have learned that the immune-system is the key to reduce the severity of COVID-19 and, through its modulation, it has been possible saving people's life. In this short communication, we discuss the use of nutraceuticals to modulate and stimulate the immune answer for reducing the severity of COVID-19 symptoms. The nutraceuticals are safe and can be administered to all ages. In addition, combination of natural anti-viral elements and immune-stimulating molecules already successfully tested against others upper-respiratory tract infections-could be efficient against SARS-CoV2. We believe that these natural molecules could really be a valid ally against COVID-19, especially in this moment in which a SARS-CoV2 vaccine is still not available.


Assuntos
Infecções por Coronavirus/terapia , Suplementos Nutricionais , Pneumonia Viral/terapia , Antivirais/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Lactobacillus/fisiologia , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Selênio/farmacologia , Selênio/uso terapêutico , Índice de Gravidade de Doença , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Replicação Viral/efeitos dos fármacos
10.
J Chem Phys ; 153(11): 115101, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32962355

RESUMO

Broad-spectrum antiviral drugs are urgently needed to stop the Coronavirus Disease 2019 pandemic and prevent future ones. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is related to the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), which have caused the previous outbreaks. The papain-like protease (PLpro) is an attractive drug target due to its essential roles in the viral life cycle. As a cysteine protease, PLpro is rich in cysteines and histidines, and their protonation/deprotonation modulates catalysis and conformational plasticity. Here, we report the pKa calculations and assessment of the proton-coupled conformational dynamics of SARS-CoV-2 in comparison to SARS-CoV and MERS-CoV PLpros using the recently developed graphical processing unit (GPU)-accelerated implicit-solvent continuous constant pH molecular dynamics method with a new asynchronous replica-exchange scheme, which allows computation on a single GPU card. The calculated pKa's support the catalytic roles of the Cys-His-Asp triad. We also found that several residues can switch protonation states at physiological pH among which is C270/271 located on the flexible blocking loop 2 (BL2) of SARS-CoV-2/CoV PLpro. Simulations revealed that the BL2 can open and close depending on the protonation state of C271/270, consistent with the most recent crystal structure evidence. Interestingly, despite the lack of an analogous cysteine, BL2 in MERS-CoV PLpro is also very flexible, challenging a current hypothesis. These findings are supported by the all-atom fixed-charge simulations and provide a starting point for more detailed studies to assist the structure-based design of broad-spectrum inhibitors against CoV PLpros.


Assuntos
Antivirais/farmacologia , Betacoronavirus/enzimologia , Desenho de Fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/enzimologia , Simulação de Dinâmica Molecular , Papaína/química , Papaína/metabolismo , Prótons , Sequência de Aminoácidos , Histidina , Concentração de Íons de Hidrogênio , Papaína/antagonistas & inibidores , Domínios Proteicos
11.
Food Funct ; 11(9): 7415-7420, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32966484

RESUMO

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread around the world at an unprecedented rate. In the present study, 4 marine sulfated polysaccharides were screened for their inhibitory activity against SARS-CoV-2, including sea cucumber sulfated polysaccharide (SCSP), fucoidan from brown algae, iota-carrageenan from red algae, and chondroitin sulfate C from sharks (CS). Of them, SCSP, fucoidan, and carrageenan showed significant antiviral activities at concentrations of 3.90-500 µg mL-1. SCSP exhibited the strongest inhibitory activity with IC50 of 9.10 µg mL-1. Furthermore, a test using pseudotype virus with S glycoprotein confirmed that SCSP could bind to the S glycoprotein to prevent SARS-CoV-2 host cell entry. The three antiviral polysaccharides could be employed to treat and prevent COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Feófitas/química , Polissacarídeos/farmacologia , Rodófitas/química , Pepinos-do-Mar/química , Animais , Antivirais/química , Betacoronavirus/fisiologia , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/virologia , Polissacarídeos/química , Tubarões , Sulfatos/química , Internalização do Vírus/efeitos dos fármacos
12.
Drug Des Devel Ther ; 14: 3803-3813, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32982184

RESUMO

Objective: This study aimed to evaluate the pharmacological mechanisms of antiviral drugs against the novel coronavirus disease (COVID-19) and the study designs in clinical trials registered with the International Clinical Trials Registry Platform (ICTRP). Methods: Clinical trials involving antiviral drugs for treating COVID-19 were retrieved from the ICTRP database. For each trial, the study design, number of participants, primary endpoints, source register, antiviral mechanism, and results were evaluated. Results: On June 10, 2020, 145 eligible clinical trials were retrieved from the ICTRP, of which 99 (68.3%) were randomized trials, 109 (75.2%) were parallel assignment trials, 38 (26.2%) were double or single blinded, 130 (89.7%) involved two groups, and 75 (51.6%) included more than 100 participants; and clinical improvement or recovery and virus-negative conversion were the two most common endpoints, accounting for 40.7% and 18.6%, respectively. The drugs were divided according to the antiviral mechanism into HIV reverse transcriptase inhibitors, RNA-dependent RNA polymerase inhibitors, HIV protease inhibitors (PIs), hepatitis C virus NS3 PIs, and anti-influenza drugs. Conclusion: The design characteristics of clinical trials of antiviral drugs for treating COVID-19 as well as the mechanism of action and antiviral efficacy of the drugs were evaluated in this study. The results of these trials could constitute a reference for future clinical trials to be executed on COVID-19 treatment and prevention.


Assuntos
Antivirais/uso terapêutico , Ensaios Clínicos como Assunto , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Sistema de Registros , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Coleta de Dados , Interpretação Estatística de Dados , Gerenciamento de Dados , Combinação de Medicamentos , Humanos , Pandemias , Projetos de Pesquisa
13.
Rev Med Suisse ; 16(704): 1538-1543, 2020 Sep 02.
Artigo em Francês | MEDLINE | ID: mdl-32880108

RESUMO

Hepatitis D virus causes chronic hepatitis D. The virus is defective, meaning it requires simultaneous presence of hepatitis B virus within the hepatocytes to complete its viral cycle. Globally, 15 to 20 millions people are estimated to be chronically co-infected by hepatitis B and D viruses. Current therapy remains limited to pegylated interferon alfa, which has an unsatisfactory success rate, several contraindications and many side effects. Drugs directly targeting the hepatitis D virus life cycle are being developed with promising results. These drugs target viral entry into hepatocytes, virion assembly or secretion from infected hepatocytes. This article provides an overview of the newly developed therapies and their efficacy.


Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Hepatite D Crônica/tratamento farmacológico , Vírus Delta da Hepatite/efeitos dos fármacos , Hepatite B Crônica/virologia , Hepatite D Crônica/virologia , Humanos , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico
14.
Nat Commun ; 11(1): 4417, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887884

RESUMO

COVID-19 was declared a pandemic on March 11 by WHO, due to its great threat to global public health. The coronavirus main protease (Mpro, also called 3CLpro) is essential for processing and maturation of the viral polyprotein, therefore recognized as an attractive drug target. Here we show that a clinically approved anti-HCV drug, Boceprevir, and a pre-clinical inhibitor against feline infectious peritonitis (corona) virus (FIPV), GC376, both efficaciously inhibit SARS-CoV-2 in Vero cells by targeting Mpro. Moreover, combined application of GC376 with Remdesivir, a nucleotide analogue that inhibits viral RNA dependent RNA polymerase (RdRp), results in sterilizing additive effect. Further structural analysis reveals binding of both inhibitors to the catalytically active side of SARS-CoV-2 protease Mpro as main mechanism of inhibition. Our findings may provide critical information for the optimization and design of more potent inhibitors against the emerging SARS-CoV-2 virus.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Prolina/análogos & derivados , Inibidores de Proteases/farmacologia , Pirrolidinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacologia , Betacoronavirus/enzimologia , Sítios de Ligação/efeitos dos fármacos , Domínio Catalítico , Chlorocebus aethiops , Cristalografia por Raios X , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Modelos Animais de Doenças , Ensaios de Triagem em Larga Escala , Modelos Moleculares , Pandemias , Prolina/farmacologia , RNA Replicase/antagonistas & inibidores , RNA Replicase/química , RNA Replicase/metabolismo , Células Vero , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
15.
Molecules ; 25(18)2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32911757

RESUMO

The epidemic, caused by SARS-CoV-2 at the beginning of 2020, led us to a serious change in our lifestyle that for about three months has confined us to our homes, far from our laboratory routine. In this period, the belief that the work of a researcher should never stop has been the driving force in writing the present paper. It aims at reviewing the recent scientific knowledge about in vitro experimental data that focused on the antiviral role of phenols and polyphenols against different species of coronaviruses (CoVs), pointing up the viral targets potentially involved. In the current literature scenario, the papain-like and the 3-chymotrypsin-like proteases seem to be the most deeply investigated and a number of isolated natural (poly)phenols has been screened for their efficacy.


Assuntos
Antivirais/farmacologia , Pesquisa Biomédica/tendências , Coronavirus/efeitos dos fármacos , Polifenóis/farmacologia , Animais , Betacoronavirus/efeitos dos fármacos , Quimases/uso terapêutico , Humanos
16.
Nat Commun ; 11(1): 4682, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943628

RESUMO

The ongoing Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emphasized the urgent need for antiviral therapeutics. The viral RNA-dependent-RNA-polymerase (RdRp) is a promising target with polymerase inhibitors successfully used for the treatment of several viral diseases. We demonstrate here that Favipiravir predominantly exerts an antiviral effect through lethal mutagenesis. The SARS-CoV RdRp complex is at least 10-fold more active than any other viral RdRp known. It possesses both unusually high nucleotide incorporation rates and high-error rates allowing facile insertion of Favipiravir into viral RNA, provoking C-to-U and G-to-A transitions in the already low cytosine content SARS-CoV-2 genome. The coronavirus RdRp complex represents an Achilles heel for SARS-CoV, supporting nucleoside analogues as promising candidates for the treatment of COVID-19.


Assuntos
Amidas/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Pirazinas/farmacologia , Amidas/farmacocinética , Animais , Antivirais/farmacocinética , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Modelos Moleculares , Mutagênese/efeitos dos fármacos , Pandemias , Pneumonia Viral/virologia , Pirazinas/farmacocinética , RNA Replicase/química , RNA Replicase/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Análise de Sequência , Células Vero , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
17.
Biomolecules ; 10(9)2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32967116

RESUMO

We report the results of our in silico study of approved drugs as potential treatments for COVID-19. The study is based on the analysis of normal modes of proteins. The drugs studied include chloroquine, ivermectin, remdesivir, sofosbuvir, boceprevir, and α-difluoromethylornithine (DMFO). We applied the tools we developed and standard tools used in the structural biology community. Our results indicate that small molecules selectively bind to stable, kinetically active residues and residues adjoining them on the surface of proteins and inside protein pockets, and that some prefer hydrophobic sites over other active sites. Our approach is not restricted to viruses and can facilitate rational drug design, as well as improve our understanding of molecular interactions, in general.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/química , Alanina/farmacologia , Anticorpos Antivirais/imunologia , Reações Antígeno-Anticorpo , Antivirais/química , Antivirais/uso terapêutico , Betacoronavirus , Sítios de Ligação , Cloroquina/química , Cloroquina/farmacologia , Infecções por Coronavirus/prevenção & controle , Reposicionamento de Medicamentos , Eflornitina/química , Eflornitina/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ivermectina/química , Ivermectina/farmacologia , L-Lactato Desidrogenase/química , L-Lactato Desidrogenase/efeitos dos fármacos , Modelos Moleculares , Simulação de Acoplamento Molecular , Pandemias/prevenção & controle , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral/prevenção & controle , Prolina/análogos & derivados , Prolina/química , Prolina/farmacologia , Ligação Proteica , Conformação Proteica , Mapeamento de Interação de Proteínas , Receptores da Glicina/química , Receptores da Glicina/efeitos dos fármacos , Saposinas/química , Saposinas/efeitos dos fármacos , Sofosbuvir/química , Sofosbuvir/farmacologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/efeitos dos fármacos , Relação Estrutura-Atividade
18.
Virol J ; 17(1): 136, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32907596

RESUMO

BACKGROUND: Coronaviruses (CoVs) were long thought to only cause mild respiratory and gastrointestinal symptoms in humans but outbreaks of Middle East Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (SARS)-CoV-1, and the recently identified SARS-CoV-2 have cemented their zoonotic potential and their capacity to cause serious morbidity and mortality, with case fatality rates ranging from 4 to 35%. Currently, no specific prophylaxis or treatment is available for CoV infections. Therefore we investigated the virucidal and antiviral potential of Echinacea purpurea (Echinaforce®) against human coronavirus (HCoV) 229E, highly pathogenic MERS- and SARS-CoVs, as well as the newly identified SARS-CoV-2, in vitro. METHODS: To evaluate the antiviral potential of the extract, we pre-treated virus particles and cells and evaluated remaining infectivity by limited dilution. Furthermore, we exposed cells to the extract after infection to further evaluate its potential as a prophylaxis and treatment against coronaviruses. We also determined the protective effect of Echinaforce® in re-constituted nasal epithelium. RESULTS: In the current study, we found that HCoV-229E was irreversibly inactivated when exposed to Echinaforce® at 3.2 µg/ml IC50. Pre-treatment of cell lines, however, did not inhibit infection with HCoV-229E and post-infection treatment had only a marginal effect on virus propagation at 50 µg/ml. However, we did observe a protective effect in an organotypic respiratory cell culture system by exposing pre-treated respiratory epithelium to droplets of HCoV-229E, imitating a natural infection. The observed virucidal activity of Echinaforce® was not restricted to common cold coronaviruses, as both SARS-CoV-1 and MERS-CoVs were inactivated at comparable concentrations. Finally, the causative agent of COVID-19, SARS-CoV-2 was also inactivated upon treatment with 50µg/ml Echinaforce®. CONCLUSIONS: These results show that Echinaforce® is virucidal against HCoV-229E, upon direct contact and in an organotypic cell culture model. Furthermore, MERS-CoV and both SARS-CoV-1 and SARS-CoV-2 were inactivated at similar concentrations of the extract. Therefore we hypothesize that Echinacea purpurea preparations, such as Echinaforce®, could be effective as prophylactic treatment for all CoVs due to their structural similarities.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Coronavirus Humano 229E/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Coronavirus/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Linhagem Celular , Chlorocebus aethiops , Resfriado Comum/tratamento farmacológico , Resfriado Comum/virologia , Infecções por Coronavirus/virologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Vírus de RNA/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia , Células Vero
19.
Antivir Chem Chemother ; 28: 2040206620961712, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972196

RESUMO

Macrolides are a large group of antibiotics characterised by the presence of a macro-lactone ring of variable size. The prototype of macrolide antibiotics, erythromycin was first produced by Streptomyces and associated species more than half a century ago; other related drugs were developed. These drugs have been shown to have several pharmacological properties: in addition to their antibiotic activity, they possess some anti-inflammatory properties and have been also considered against non-bacterial infections. In this review, we analysed the available clinical evidences regarding the potential anti-viral activity of macrolides, by focusing on erythromycin, clarithromycin and azithromycin. Overall, there is no significant evidences so far that macrolides might have a direct benefit on most of viral infections considered in this review (RSV, Influenza, coronaviruses, Ebola and Zika viruses). However, their clinical benefit cannot be ruled out without further and focused clinical studies. Macrolides may improve the clinical course of viral respiratory infections somehow, at least through indirect mechanisms relying on some and variable anti-inflammatory and/or immunomodulatory effects, in addition to their well-known antibacterial activity.


Assuntos
Antibacterianos/farmacologia , Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Macrolídeos/farmacologia , Pneumonia Viral/tratamento farmacológico , Animais , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Antivirais/farmacocinética , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Humanos , Macrolídeos/farmacocinética , Macrolídeos/uso terapêutico , Pandemias
20.
Drug Res (Stuttg) ; 70(10): 484-488, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32877948

RESUMO

Although the major therapeutic uses of the proton pump inhibitors are in gastric-acid related diseases, evidences are suggestive of a pleiotropic nature of the compounds. We comment on the probable pathways and cellular machineries via which proton pump inhibitors could show beneficial therapeutic effects against SARS-CoV-2 based on the existing evidences. Proton pump inhibitors have shown antiviral potencies in various in vivo and in vitro studies. Some of the major possible ways through which they can act against SARS-CoV-2 are by exerting anti-inflammatory and anti-fibrotic effects, via vacuolar ATPase pumps leading to raised endolysosomal pH and by targeting endosomal complexes. The current pandemic has put forward a challenge to find treatment options. Although the potential roles of proton pump inhibitors against SARS-CoV-2 have been discussed in recent publications, the clinical evidences for their real-world effectiveness do not point towards a beneficial effect clearly yet. We suggest that although proton pump inhibitors should strongly be considered as potential therapeutic options for COVID-19, larger studies in the form of randomized controlled trials would be required to arrive at a definite conclusion.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Inibidores da Bomba de Prótons/farmacologia , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/virologia
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