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1.
Sci Rep ; 10(1): 16577, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024223

RESUMO

SARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2. We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase. Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells; additionally, COVID-19 clinical trials with EPCLUSA and with Sofosbuvir plus Daclatasvir have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity. Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Exonucleases/metabolismo , Pneumonia Viral/tratamento farmacológico , Pró-Fármacos/farmacologia , RNA Viral/efeitos dos fármacos , Sofosbuvir/farmacologia , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/química , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/química , Antivirais/uso terapêutico , Betacoronavirus/enzimologia , Infecções por Coronavirus/virologia , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Pandemias , Pneumonia Viral/virologia , Pró-Fármacos/uso terapêutico , RNA Replicase/antagonistas & inibidores , RNA Replicase/metabolismo , RNA Viral/química , RNA Viral/metabolismo , Sofosbuvir/química , Sofosbuvir/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
2.
Pharmacol Rev ; 72(4): 862-898, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32929000

RESUMO

RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.


Assuntos
RNA/efeitos dos fármacos , RNA/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Aptâmeros de Nucleotídeos/uso terapêutico , Betacoronavirus , Técnicas de Química Analítica/métodos , Técnicas de Química Analítica/normas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Infecções por Coronavirus/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Desenvolvimento de Medicamentos/organização & administração , Descoberta de Drogas , Humanos , MicroRNAs/farmacologia , MicroRNAs/uso terapêutico , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , RNA/efeitos adversos , RNA Antissenso/farmacologia , RNA Antissenso/uso terapêutico , RNA Guia/farmacologia , RNA Guia/uso terapêutico , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/farmacologia , RNA Ribossômico/efeitos dos fármacos , RNA Ribossômico/farmacologia , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , RNA Viral/efeitos dos fármacos , Ribonucleases/metabolismo , Riboswitch/efeitos dos fármacos
3.
Int J Mol Sci ; 21(16)2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32824072

RESUMO

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a severe global health crisis. In this paper, we used docking and simulation methods to identify potential targets and the mechanism of action of chloroquine (CQ) and hydroxychloroquine (HCQ) against SARS-CoV-2. Our results showed that both CQ and HCQ influenced the functionality of the envelope (E) protein, necessary in the maturation processes of the virus, due to interactions that modify the flexibility of the protein structure. Furthermore, CQ and HCQ also influenced the proofreading and capping of viral RNA in SARS-CoV-2, performed by nsp10/nsp14 and nsp10/nsp16. In particular, HCQ demonstrated a better energy binding with the examined targets compared to CQ, probably due to the hydrogen bonding of the hydroxyl group of HCQ with polar amino acid residues.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Cloroquina/farmacologia , Exorribonucleases/metabolismo , Hidroxicloroquina/farmacologia , Metiltransferases/metabolismo , Proteínas não Estruturais Virais/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , RNA Viral/efeitos dos fármacos , RNA Viral/genética , Proteínas do Envelope Viral/efeitos dos fármacos , Proteínas do Envelope Viral/metabolismo , Replicação Viral/efeitos dos fármacos
4.
Sci Rep ; 10(1): 13689, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792492

RESUMO

To describe the epidemiological and clinical characteristics of patients with Corona Virus Disease 2019 (COVID-19) in Beijing. To analyze the application of corticosteroids in patients with severe pneumonia. We collected information on demographic characteristics, exposure history, clinical characteristics, corticosteroids use, and outcomes of the 65 confirmed cases of COVID-19 at Fifth Medical Center of PLA General Hospital from Jan 20 to Feb 23, 2020. The final follow-up date observed was April 15th, 2020. The number of patients with mild, general, severe, and critical type were 10 (15.38%), 32 (49.23%), 8 (12.31%), and 15 (23.08%), respectively. The median incubation period was 6 days. Notable outliers were 1 patient at 16 days and 1 patient at 21 days. In lymphocyte subgroup analysis, decreases in total, T, CD4, and CD8 lymphocytes were more common as the disease worsened (All P < 0.05). Methylprednisolone (mPSL) was applied to 31 (47.69%) patients with pneumonia, including 10 (31.25%) general, 8 (100%) severe, and 13 (86.67%) critical patients, respectively. Corticosteroids inhibited Interleukin-6(IL-6) production (P = 0.0215) but did not affect T lymphocyte (P = 0.0796). There was no significant difference between patients using lower dose (≤ 2 mg/kg day) and higher dose (> 2 mg/kg day) mPSL in inhibiting IL-6 production (P = 0.5856). Thirty of 31 patients (96.77%) had stopped mPSL due to improvement of pneumonia. Virus RNA clearance time lengthened with disease progression (P = 0.0001). In general type, there was no significant difference in virus clearance time between patients with (15, 12-19 days) and without (14.5, 11-18 days) (P = 0.7372) mPSL use. Lymphocyte, especially T lymphocyte, in severe and critical patients showed a dramatic decrease. Application of lower dose corticosteroids (≤ 2 mg/kg day) could inhibit IL-6 production (a representative of cytokines) as effectively as a higher dose. Proper use corticosteroids in general type patients did not delay virus clearance.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Glucocorticoides/uso terapêutico , Metilprednisolona/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Adolescente , Adulto , Idoso , Pequim/epidemiologia , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Criança , Pré-Escolar , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacologia , Humanos , Interleucina-6/antagonistas & inibidores , Contagem de Linfócitos , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/farmacologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , RNA Viral/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem
5.
Cell Death Dis ; 11(8): 656, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32814759

RESUMO

The current epidemic of coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) calls for the development of inhibitors of viral replication. Here, we performed a bioinformatic analysis of published and purported SARS-CoV-2 antivirals including imatinib mesylate that we found to suppress SARS-CoV-2 replication on Vero E6 cells and that, according to the published literature on other coronaviruses is likely to act on-target, as a tyrosine kinase inhibitor. We identified a cluster of SARS-CoV-2 antivirals with characteristics of lysosomotropic agents, meaning that they are lipophilic weak bases capable of penetrating into cells. These agents include cepharentine, chloroquine, chlorpromazine, clemastine, cloperastine, emetine, hydroxychloroquine, haloperidol, ML240, PB28, ponatinib, siramesine, and zotatifin (eFT226) all of which are likely to inhibit SARS-CoV-2 replication by non-specific (off-target) effects, meaning that they probably do not act on their 'official' pharmacological targets, but rather interfere with viral replication through non-specific effects on acidophilic organelles including autophagosomes, endosomes, and lysosomes. Imatinib mesylate did not fall into this cluster. In conclusion, we propose a tentative classification of SARS-CoV-2 antivirals into specific (on-target) versus non-specific (off-target) agents based on their physicochemical characteristics.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Pneumonia Viral/metabolismo , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/farmacologia , Morte Celular/efeitos dos fármacos , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Hidroxicloroquina/farmacologia , Mesilato de Imatinib/farmacologia , Lisossomos/efeitos dos fármacos , Pandemias , Pneumonia Viral/virologia , Inibidores de Proteínas Quinases/farmacologia , RNA Viral/efeitos dos fármacos , Células Vero , Carga Viral/efeitos dos fármacos
6.
In Vivo ; 34(3 Suppl): 1593-1596, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-536995

RESUMO

The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virally-induced T-cell- and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Liases de Carbono-Enxofre/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Metionina/metabolismo , Pneumonia Viral/tratamento farmacológico , Capuzes de RNA/efeitos dos fármacos , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , RNA Viral/efeitos dos fármacos , Administração Oral , Antivirais/administração & dosagem , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/uso terapêutico , Betacoronavirus/fisiologia , Liases de Carbono-Enxofre/administração & dosagem , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Metanálise como Assunto , Metilação/efeitos dos fármacos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pseudomonas putida/enzimologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , S-Adenosilmetionina/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Replicação Viral/efeitos dos fármacos
7.
In Vivo ; 34(3 Suppl): 1593-1596, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32503816

RESUMO

The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virally-induced T-cell- and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Liases de Carbono-Enxofre/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Metionina/metabolismo , Pneumonia Viral/tratamento farmacológico , Capuzes de RNA/efeitos dos fármacos , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , RNA Viral/efeitos dos fármacos , Administração Oral , Antivirais/administração & dosagem , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/uso terapêutico , Betacoronavirus/fisiologia , Liases de Carbono-Enxofre/administração & dosagem , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Metanálise como Assunto , Metilação/efeitos dos fármacos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pseudomonas putida/enzimologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , S-Adenosilmetionina/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Replicação Viral/efeitos dos fármacos
8.
Int J STD AIDS ; 31(7): 694-698, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32538333

RESUMO

Human immunodeficiency virus (HIV) ribonucleic acid (RNA) levels generally remain undetectable in the cerebrospinal fluid of people living with HIV with peripheral viral suppression. Secondary HIV central nervous system (CNS) escape refers to the rare independent replication of HIV RNA in the central nervous system despite peripheral viral suppression that occurs in the setting of a concomitant non-HIV infection. We describe here a young man with perinatal HIV infection considered a viral controller who developed secondary HIV CNS escape in the setting of a presumed fungal CNS infection.


Assuntos
Antirretrovirais/uso terapêutico , Sistema Nervoso Central/virologia , Líquido Cefalorraquidiano/virologia , Infecções por HIV/líquido cefalorraquidiano , Infecções por HIV/tratamento farmacológico , Cefaleia/etiologia , Fotofobia/etiologia , Carga Viral/efeitos dos fármacos , Replicação Viral/genética , Adulto , Antifúngicos/uso terapêutico , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/fisiopatologia , Infecções por HIV/virologia , Humanos , Masculino , Micoses/tratamento farmacológico , RNA Viral/líquido cefalorraquidiano , RNA Viral/efeitos dos fármacos , RNA Viral/genética , Resultado do Tratamento
9.
Proc Natl Acad Sci U S A ; 117(27): 15763-15771, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571938

RESUMO

HIV-1 latency is a major barrier to cure. Identification of small molecules that destabilize latency and allow immune clearance of infected cells could lead to treatment-free remission. In vitro models of HIV-1 latency involving cell lines or primary cells have been developed for characterization of HIV-1 latency and high-throughput screening for latency-reversing agents (LRAs). We have shown that the majority of LRAs identified to date are relatively ineffective in cells from infected individuals despite activity in model systems. We show here that, for diverse LRAs, latency reversal observed in model systems involves a heat shock factor 1 (HSF1)-mediated stress pathway. Small-molecule inhibition of HSF1 attenuated HIV-1 latency reversal by histone deactylase inhibitors, protein kinase C agonists, and proteasome inhibitors without interfering with the known mechanism of action of these LRAs. However, latency reversal by second mitochondria-derived activator of caspase (SMAC) mimetics was not affected by inhibition of HSF1. In cells from infected individuals, inhibition of HSF1 attenuated latency reversal by phorbol ester+ionomycin but not by anti-CD3+anti-CD28. HSF1 promotes elongation of HIV-1 RNA by recruiting P-TEFb to the HIV-1 long terminal repeat (LTR), and we show that inhibition of HSF1 attenuates the formation of elongated HIV-1 transcripts. We demonstrate that in vitro models of latency have higher levels of the P-TEFb subunit cyclin T1 than primary cells, which may explain why many LRAs are functional in model systems but relatively ineffective in primary cells. Together, these studies provide insights into why particular LRA combinations are effective in reversing latency in cells from infected individuals.


Assuntos
Infecções por HIV/genética , HIV-1/genética , Fatores de Transcrição de Choque Térmico/genética , Latência Viral/genética , Fármacos Anti-HIV/farmacologia , Proteínas Reguladoras de Apoptose/genética , Ciclina T/genética , Infecções por HIV/virologia , HIV-1/patogenicidade , Fatores de Transcrição de Choque Térmico/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Humanos , Proteínas Mitocondriais/genética , Fator B de Elongação Transcricional Positiva/genética , Proteína Quinase C/genética , RNA Viral/efeitos dos fármacos , RNA Viral/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Sequências Repetidas Terminais/genética , Ativação Viral/genética
10.
Eur Heart J Acute Cardiovasc Care ; 9(3): 209-214, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: covidwho-165340

RESUMO

Therapeutic options for coronavirus disease 2019 are desperately needed to respond to the ongoing severe acute respiratory syndrome coronavirus 2 pandemic. Both antiviral drugs and immunomodulators might have their place in the management of coronavirus disease 2019. Unfortunately, no drugs have been approved yet to treat infections with human coronaviruses. As it will take years to develop new therapies for severe acute respiratory syndrome coronavirus 2, the current focus is on the repurposing of drugs that have been approved or are in development for other conditions. Several clinical trials have already been conducted or are currently ongoing to evaluate the efficacy of such drugs. Here, we discuss the potential of these therapies for the treatment of coronavirus disease 2019.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Betacoronavirus/efeitos dos fármacos , Cloroquina/toxicidade , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Administração Intravenosa , Alanina/administração & dosagem , Alanina/farmacologia , Alanina/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/administração & dosagem , Antivirais/farmacologia , Antivirais/uso terapêutico , Cloroquina/efeitos adversos , Ensaios Clínicos como Assunto , Infecções por Coronavirus/epidemiologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Pandemias , Pneumonia Viral/epidemiologia , Pirazinas/farmacologia , Pirazinas/uso terapêutico , RNA Viral/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
11.
Arch Med Res ; 51(6): 585-586, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32439198

RESUMO

COVID-19 is now pandemic throughout the world. Scientist, doctors are searching for effective therapy of this diseases. The remdesivir, an antiviral drug, is appeared as 'molecule of hope' for the treatment of this disease. USFDA gave emergency approval to this drug for the treatment of COVID-19. The molecular mechanism is unknown. In this paper, we tried to describe the probable molecular mechanism of remdesivir to inhibit the RNA synthesis of SARS-CoV-2. However, more detail mechanism is needed to understand mechanism of action of remdesivir.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Humanos , Pandemias , RNA Viral/efeitos dos fármacos
12.
Eur Heart J Acute Cardiovasc Care ; 9(3): 209-214, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32363880

RESUMO

Therapeutic options for coronavirus disease 2019 are desperately needed to respond to the ongoing severe acute respiratory syndrome coronavirus 2 pandemic. Both antiviral drugs and immunomodulators might have their place in the management of coronavirus disease 2019. Unfortunately, no drugs have been approved yet to treat infections with human coronaviruses. As it will take years to develop new therapies for severe acute respiratory syndrome coronavirus 2, the current focus is on the repurposing of drugs that have been approved or are in development for other conditions. Several clinical trials have already been conducted or are currently ongoing to evaluate the efficacy of such drugs. Here, we discuss the potential of these therapies for the treatment of coronavirus disease 2019.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Betacoronavirus/efeitos dos fármacos , Cloroquina/toxicidade , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Administração Intravenosa , Alanina/administração & dosagem , Alanina/farmacologia , Alanina/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/administração & dosagem , Antivirais/farmacologia , Antivirais/uso terapêutico , Cloroquina/efeitos adversos , Ensaios Clínicos como Assunto , Infecções por Coronavirus/epidemiologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Pandemias , Pneumonia Viral/epidemiologia , Pirazinas/farmacologia , Pirazinas/uso terapêutico , RNA Viral/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
14.
Chem Commun (Camb) ; 55(93): 14027-14030, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31690898

RESUMO

RNA-biased small molecules with a monoquinoxaline core target the L-shaped structure of subdomain IIa of Hepatitis C virus internal ribosome entry site (IRES) RNA in proximity to the Mg2+ binding site. The binding event leads to the destacking of RNA bases, resulting in the inhibition of IRES-mediated translation and HCV RNA replication.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Sítios Internos de Entrada Ribossomal/efeitos dos fármacos , Quinoxalinas/farmacologia , RNA Viral/efeitos dos fármacos , Antivirais/química , Hepacivirus/genética , Humanos , Sítios Internos de Entrada Ribossomal/genética , Conformação Molecular , Quinoxalinas/química , RNA Viral/genética , Replicação Viral/efeitos dos fármacos
15.
Eur J Med Chem ; 184: 111733, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31604163

RESUMO

Norovirus (NV), is the most common cause of acute gastroenteritis worldwide. To date, there is no specific anti-NV drug or vaccine to treat NV infections. In this study, we evaluated the inhibitory effect of different stilbene-based analogs on RNA genome replication of human NV (HNV) using a virus replicon-bearing cell line (HG23). Initial screening of our in-house chemical library against NV led to the identification of a hit containing stilbene scaffold 5 which on initial optimization gave us a vinyl stilbene compound 16c (EC50 = 4.4 µM). Herein we report our structure-activity relationship study of the novel series of vinyl stilbene analogs that inhibits viral RNA genome replication in a human NV-specific manner. Among these newly synthesized compounds, several amide derivatives of vinyl stilbenes exhibited potent anti-NV activity with EC50 values ranging from 1 to 2 µM. A trans-vinyl stilbenoid with an appended substituted piperazine amide (18k), exhibited potent anti-NV activity and also displayed favorable metabolic stability. Compound 18k demonstrated an excellent safety profile, the highest suppressive effect, and was selective for HNV replication via a viral RNA polymerase-independent manner. Its potential host-targeting antiviral mechanism was further supported by specific activation of heat shock factor 1-dependent stress-inducible pathway by 18k. These results suggest that 18k might be a promising lead compound for developing novel NV inhibitors with the novel antiviral mechanism.


Assuntos
Antivirais/farmacologia , Norovirus/efeitos dos fármacos , Estilbenos/farmacologia , Compostos de Vinila/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos/efeitos dos fármacos , Microssomos/microbiologia , Estrutura Molecular , Células RAW 264.7 , RNA Viral/efeitos dos fármacos , RNA Viral/genética , Estilbenos/química , Relação Estrutura-Atividade , Compostos de Vinila/química , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
16.
BMC Vet Res ; 15(1): 318, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488163

RESUMO

BACKGROUND: Bovine viral diarrhoea virus (BVDV), an enveloped, single-stranded, positive-sense RNA virus from the Flaviviridae family, is a globally distributed bovine pathogen. BVDV infection in cattle, despite having a wide range of clinical manifestations, is invariably responsible for significant economic losses. To counteract these losses, various schemes to control and eradicate BVDV have been implemented, although safe drugs effectively inhibiting the replication of the virus are still lacking. The purpose of this study was to characterize the antiviral effect of naturally occurring proteins and peptide, such as bovine lactoferrin, chicken egg lysozyme, and nisin from Lactococcus lactis, used both individually and in combination, against the cytopathic NADL strain of BVDV in vitro. After determining the cytotoxicity level of each protein or peptide to MDBK cells, its antiviral effects were evaluated using virucidal, cytopathic effect inhibition and viral yield reduction assays. In addition, the influence of the tested compounds on the intracellular viral RNA level was determined. RESULTS: The highest efficacy among the single treatments was achieved by bovine lactoferrin, which was effective both at the early stages of viral infection and during its entire course, although the effect weakened over time. Nisin and lysozyme were effective at later stages of infection, and the intensity of their effect did not diminish with time. Nisin+lactoferrin and lysozyme+lactoferrin combinations demonstrated stronger antiviral effects than did the single substances. The nisin+lactoferrin mixture present during the whole period of infection produced the strongest anti-BVDV effect in our entire research on both the extracellular viral titre (titre reduction up to 2.875 log ≈ 99.9%) and the intracellular viral RNA level (reduction up to 89%), and this effect intensified over the incubation time. CONCLUSIONS: The tested substances could be applied in bovine viral diarrhoea prevention and therapy, especially when used in combination.


Assuntos
Antivirais/farmacologia , Vírus da Diarreia Viral Bovina/efeitos dos fármacos , Lactoferrina/farmacologia , Muramidase/farmacologia , Nisina/farmacologia , Animais , Antivirais/toxicidade , Bovinos , Linhagem Celular , Citotoxinas/farmacocinética , Citotoxinas/toxicidade , Vírus da Diarreia Viral Bovina/genética , Lactoferrina/toxicidade , Muramidase/toxicidade , Nisina/toxicidade , RNA Viral/biossíntese , RNA Viral/efeitos dos fármacos
17.
Cell Host Microbe ; 26(2): 217-227.e6, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31415754

RESUMO

How the covalent modification of mRNA ribonucleotides, termed epitranscriptomic modifications, alters mRNA function remains unclear. One issue has been the difficulty of quantifying these modifications. Using purified HIV-1 genomic RNA, we show that this RNA bears more epitranscriptomic modifications than the average cellular mRNA, with 5-methylcytosine (m5C) and 2'O-methyl modifications being particularly prevalent. The methyltransferase NSUN2 serves as the primary writer for m5C on HIV-1 RNAs. NSUN2 inactivation inhibits not only m5C addition to HIV-1 transcripts but also viral replication. This inhibition results from reduced HIV-1 protein, but not mRNA, expression, which in turn correlates with reduced ribosome binding to viral mRNAs. In addition, loss of m5C dysregulates the alternative splicing of viral RNAs. These data identify m5C as a post-transcriptional regulator of both splicing and function of HIV-1 mRNA, thereby affecting directly viral gene expression.


Assuntos
5-Metilcitosina/farmacologia , Regulação Viral da Expressão Gênica , HIV-1/genética , RNA Viral/metabolismo , Transcriptoma , 5-Metilcitosina/metabolismo , Linfócitos T CD4-Positivos , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Metiltransferases/farmacologia , Processamento de RNA , RNA Mensageiro/metabolismo , RNA Viral/efeitos dos fármacos , Vírion , Replicação Viral/efeitos dos fármacos
18.
Biol Pharm Bull ; 42(5): 770-777, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061319

RESUMO

Previously, we reported that coffee extract and its constituents, caffeic acid (CA) and p-coumaric acid, inhibit infection by the hepatitis C virus (HCV). In the present report, we identified another coffee-related compound, tannic acid (TA), which also inhibits HCV infection. We systematically evaluated which steps of the viral lifecycle were affected by CA and TA. TA substantially inhibits HCV RNA replication and egression, while CA does not. The infectivity of the HCV pretreated with CA or TA was almost lost. Cellular attachment of HCV particles and their interaction with apolipoprotein E, which is essential for HCV infectivity, were significantly reduced by CA. These results indicate that CA inhibits HCV entry via its direct effect on viral particles and TA inhibits HCV RNA replication and particle egression as well as entry into host cells. Taken together, our findings may provide insights into CA and TA as potential anti-HCV strategies.


Assuntos
Antivirais/farmacologia , Ácidos Cafeicos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/prevenção & controle , Taninos/farmacologia , Apolipoproteínas E/metabolismo , Linhagem Celular Tumoral , Hepacivirus/genética , Hepacivirus/metabolismo , Hepacivirus/patogenicidade , Humanos , RNA Viral/efeitos dos fármacos
19.
Antiviral Res ; 167: 13-24, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30959074

RESUMO

Zika virus (ZIKV) is a mosquito-borne virus that has garnered a lot of attention in recent years, due to the explosive epidemic from 2014 to 2016. Since its introduction in the Americas in late 2014, ZIKV has spread at an unprecedented rate and scale throughout the world and infected millions of people. Its infection has also been associated with severe neurological disorders like Guillain-Barré syndrome and microcephaly in fetuses. Despite these, there is currently no approved antiviral against ZIKV. In this study, an immunofluorescence-based high throughput screen was conducted on a library of 483 flavonoid derivatives to identify potential anti-ZIKV compounds. Flavonoids, which are natural polyphenolic compounds found in plants, represent an attractive source of antivirals due to their abundance in food and expected low toxicity. From the primary screen, three hits were selected for validation by cell viability and viral plaque reduction assays. Pinocembrin, a flavanone found in honey, tea and red wine, was chosen for downstream studies as it exhibited the strongest inhibition of ZIKV infection in human placental JEG-3 cells (IC50 = 17.4 µM). Time-course studies revealed that pinocembrin acts on post-entry process(es) of the ZIKV replication cycle. Furthermore, pinocembrin inhibits viral RNA production and envelope protein synthesis based on quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses. This study has demonstrated for the first time the in vitro anti-ZIKV activity of pinocembrin.


Assuntos
Flavanonas/farmacologia , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Animais , Antivirais/farmacologia , Linhagem Celular/virologia , Sobrevivência Celular , Feminino , Humanos , Extratos Vegetais/farmacologia , Gravidez , RNA Viral/efeitos dos fármacos , Ensaio de Placa Viral/métodos , Infecção por Zika virus/tratamento farmacológico
20.
Antiviral Res ; 167: 6-12, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30849420

RESUMO

We report the design, synthesis, and biological evaluation of a class of 1H-pyrido[2,1-b][1,3]benzothiazol-1-ones originated from compound 1, previously identified as anti-flavivirus agent. Some of the new compounds showed activity in low µM range with reasonable selectivity against Dengue 2, Yellow fever (Bolivia strain), and West Nile viruses. One of the most interesting molecules, compound 16, showed broad antiviral activity against additional flaviviruses such as Dengue 1, 3 and 4, Zika, Japanese encephalitis, several strains of Yellow fever, and tick-borne encephalitis viruses. Compound 16 did not exert any effect on alphaviruses and phleboviruses and its activity was maintained in YFV infected cells from different species. The activity of 16 appears specific for flavivirus with respect to other virus families, suggesting, but not proving, that it might be targeting a viral factor. We demonstrated that the antiviral effect of 16 is not related to reduced viral RNA synthesis or virion release. On the contrary, viral particles grown in the presence of 16 showed reduced infectivity, being unable to perform a second round of infection. The chemical class herein presented thus emerges as suitable to provide pan-flavivirus inhibitors.


Assuntos
Antivirais , Flaviviridae/efeitos dos fármacos , Oxazocinas , Piridinas , Animais , Antivirais/síntese química , Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Vírus da Encefalite Transmitidos por Carrapatos/efeitos dos fármacos , Humanos , Oxazocinas/síntese química , Oxazocinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , RNA Viral/efeitos dos fármacos , Vírion/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Vírus do Nilo Ocidental/efeitos dos fármacos , Vírus da Febre Amarela/efeitos dos fármacos , Zika virus/efeitos dos fármacos
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