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1.
Clin Transl Sci ; 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34719115

RESUMO

On October 2020, the US Food and Drug Administration (FDA) approved remdesivir as the first drug for the treatment of coronavirus disease 2019 (COVID-19), increasing remdesivir prescriptions worldwide. However, potential cardiovascular (CV) toxicities associated with remdesivir remain unknown. We aimed to characterize the CV adverse drug reactions (ADRs) associated with remdesivir using VigiBase, an individual case safety report database of the World Health Organization (WHO). Disproportionality analyses of CV-ADRs associated with remdesivir were performed using reported odds ratios and information components. We conducted in vitro experiments using cardiomyocytes derived from human pluripotent stem cell cardiomyocytes (hPSC-CMs) to confirm cardiotoxicity of remdesivir. To distinguish drug-induced CV-ADRs from COVID-19 effects, we restricted analyses to patients with COVID-19 and found that, after adjusting for multiple confounders, cardiac arrest (adjusted odds ratio [aOR]: 1.88, 95% confidence interval [CI]: 1.08-3.29), bradycardia (aOR: 2.09, 95% CI: 1.24-3.53), and hypotension (aOR: 1.67, 95% CI: 1.03-2.73) were associated with remdesivir. In vitro data demonstrated that remdesivir reduced the cell viability of hPSC-CMs in time- and dose-dependent manners. Physicians should be aware of potential CV consequences following remdesivir use and implement adequate CV monitoring to maintain a tolerable safety margin.

2.
Bioorg Med Chem Lett ; 42: 128067, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33957246

RESUMO

The outbreak of coronavirus (CoV) disease 2019 (COVID-19) caused by the severe acute respiratory syndrome CoV-2 (SARS-CoV-2) has turned into a pandemic. The enzyme 3C-like protease (3CLpro) is essential for the maturation of viral polyproteins in SARS-CoV-2 and is therefore regarded as a key drug target for treating the disease. To identify 3CLpro inhibitors that can suppress SARS-CoV-2 replication, we performed a virtual screening of 500,282 compounds in a Korean compound bank. We then subjected the top computational hits to inhibitory assays against 3CLpro in vitro, leading to the identification of a class of non-covalent inhibitors. Among these inhibitors, compound 7 showed an EC50 of 39.89 µM against SARS-CoV-2 and CC50 of 453.5 µM. This study provides candidates for the optimization of potent 3CLpro inhibitors showing antiviral effects against SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Proteases/farmacologia , SARS-CoV-2/enzimologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antivirais/metabolismo , Chlorocebus aethiops , Proteases 3C de Coronavírus/metabolismo , Avaliação Pré-Clínica de Medicamentos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Inibidores de Proteases/metabolismo , Ligação Proteica , República da Coreia , Bibliotecas de Moléculas Pequenas/metabolismo , Células Vero
3.
Antimicrob Agents Chemother ; 65(7): e0013521, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-33903104

RESUMO

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes a debilitating febrile illness characterized by persistent muscle and joint pain. The widespread distribution of transmission-competent vectors, Aedes species mosquitoes, indicates the potential risk of large-scale epidemics with high attack rates that can severely impact public health globally. Despite this, currently, there are no antivirals available for the treatment of CHIKV infections. Thus, we aimed to identify potential drug candidates by screening a chemical library using a cytopathic effect-based high-throughput screening assay. As a result, we identified radicicol, a heat shock protein 90 (Hsp90) inhibitor that effectively suppressed CHIKV replication by blocking the synthesis of both positive- and negative-strand viral RNA as well as expression of viral proteins. Interestingly, selection for viral drug-resistant variants and mutational studies revealed nonstructural protein 2 (nsP2) as a putative molecular target of radicicol. Moreover, coimmunoprecipitation and in silico modeling analyses determined that G641D mutation in the methyltransferase (MT)-like domain of nsP2 is essential for its interaction with cytoplasmic Hsp90ß chaperone. Our findings collectively support the potential application of radicicol as an anti-CHIKV agent. The detailed study of the underlying mechanism of action further contributes to our understanding of virus-host interactions for novel therapeutics against CHIKV infection.


Assuntos
Febre de Chikungunya , Vírus Chikungunya , Animais , Febre de Chikungunya/tratamento farmacológico , Vírus Chikungunya/genética , Macrolídeos , Mosquitos Vetores , Proteínas não Estruturais Virais/genética , Replicação Viral
4.
Int J Mol Sci ; 22(4)2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33557278

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) pandemic. The virus still spreads globally through human-to-human transmission. Nevertheless, there are no specific treatments clinically approved. This study aimed to compare antiviral activity of gemcitabine and its analogue 2'-fluoro-2'-deoxycytidine (2FdC) against SARS-CoV-2 as well as cytotoxicity in vitro. Fluorescent image-based antiviral assays revealed that gemcitabine was highly potent, with a 50% effective concentration (EC50) of 1.2 µM, more active than the well-known nucleoside monophosphate remdesivir (EC50 = 35.4 µM). In contrast, 2FdC was marginally active (EC50 = 175.2 µM). For all three compounds, the 50% cytotoxic concentration (CC50) values were over 300 µM toward Vero CCL-81 cells. Western blot and quantitative reverse-transcription polymerase chain reaction analyses verified that gemcitabine blocked viral protein expression in virus-infected cells, not only Vero CCL-81 cells but also Calu-3 human lung epithelial cells in a dose-dependent manner. It was found that gemcitabine has a synergistic effect when combined with remdesivir. This report suggests that the difluoro group of gemcitabine is critical for the antiviral activity and that its combination with other evaluated antiviral drugs, such as remdesivir, could be a desirable option to treat SARS-CoV-2 infection.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , COVID-19/tratamento farmacológico , Desoxicitidina/análogos & derivados , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Animais , Antivirais/farmacologia , COVID-19/metabolismo , COVID-19/virologia , Linhagem Celular , Chlorocebus aethiops , Desoxicitidina/farmacologia , Quimioterapia Combinada , Humanos , Concentração Inibidora 50 , SARS-CoV-2/fisiologia , Células Vero , Replicação Viral/efeitos dos fármacos
5.
Sci Rep ; 11(1): 821, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436985

RESUMO

Influenza virus and coronavirus, belonging to enveloped RNA viruses, are major causes of human respiratory diseases. The aim of this study was to investigate the broad spectrum antiviral activity of a naturally existing sulfated polysaccharide, lambda-carrageenan (λ-CGN), purified from marine red algae. Cell culture-based assays revealed that the macromolecule efficiently inhibited both influenza A and B viruses with EC50 values ranging from 0.3 to 1.4 µg/ml, as well as currently circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with an EC50 value of 0.9 ± 1.1 µg/ml. No toxicity to the host cells was observed at concentrations up to 300 µg/ml. Plaque titration and western blot analysis verified that λ-CGN reduced expression of viral proteins in cell lysates and suppressed progeny virus production in culture supernatants in a dose-dependent manner. This polyanionic compound exerts antiviral activity by targeting viral attachment to cell surface receptors and preventing virus entry. Moreover, its intranasal administration to mice during influenza A viral challenge not only alleviated infection-mediated reductions in body weight but also protected 60% of mice from virus-induced mortality. Thus, λ-CGN could be a promising antiviral agent for preventing infection with several respiratory viruses.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Carragenina/farmacologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Orthomyxoviridae/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/uso terapêutico , Carragenina/uso terapêutico , Cães , Feminino , Células HEK293 , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Orthomyxoviridae/fisiologia , SARS-CoV-2/fisiologia , Replicação Viral/efeitos dos fármacos
6.
Antiviral Res ; 184: 104955, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33091434

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is considered as the most significant global public health crisis of the century. Several drug candidates have been suggested as potential therapeutic options for COVID-19, including remdesivir, currently the only authorized drug for use under an Emergency Use Authorization. However, there is only limited information regarding the safety profiles of the proposed drugs, in particular drug-induced cardiotoxicity. Here, we evaluated the antiviral activity and cardiotoxicity of remdesivir using cardiomyocytes-derived from human pluripotent stem cells (hPSC-CMs) as an alternative source of human primary cardiomyocytes (CMs). In this study, remdesivir exhibited up to 60-fold higher antiviral activity in hPSC-CMs compared to Vero E6 cells; however, it also induced moderate cardiotoxicity in these cells. To gain further insight into the drug-induced arrhythmogenic risk, we assessed QT interval prolongation and automaticity of remdesivir-treated hPSC-CMs using a multielectrode array (MEA). As a result, the data indicated a potential risk of QT prolongation when remdesivir is used at concentrations higher than the estimated peak plasma concentration. Therefore, we conclude that close monitoring of the electrocardiographic/QT interval should be advised in SARS-CoV-2-infected patients under remdesivir medication, in particular individuals with pre-existing heart conditions.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , COVID-19/virologia , Miócitos Cardíacos/virologia , Células-Tronco Pluripotentes/citologia , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Amidas/farmacologia , Animais , Antimaláricos/farmacologia , COVID-19/complicações , COVID-19/tratamento farmacológico , Chlorocebus aethiops , Cloroquina/farmacologia , Eletrocardiografia , Citometria de Fluxo , Cardiopatias/complicações , Humanos , Hidroxicloroquina/farmacologia , Microscopia de Fluorescência , Miócitos Cardíacos/efeitos dos fármacos , Células-Tronco Pluripotentes/virologia , Pirazinas/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Vero , Ensaio de Placa Viral
7.
Viruses ; 12(5)2020 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-32466302

RESUMO

Influenza A virus, one of the major human respiratory pathogens, is responsible for annual seasonal endemics and unpredictable periodic pandemics. Despite the clinical availability of vaccines and antivirals, the antigenic diversity and drug resistance of this virus makes it a persistent threat to public health, underlying the need for the development of novel antivirals. In a cell culture-based high-throughput screen, a ß2-adrenergic receptor agonist, nylidrin, was identified as an antiviral compound against influenza A virus. The molecule was effective against multiple isolates of subtype H1N1, but had limited activity against subtype H3N2, depending on the strain. By examining the antiviral activity of its chemical analogues, we found that ifenprodil and clenbuterol also had reliable inhibitory effects against A/H1N1 strains. Field-based pharmacophore modeling with comparisons of active and inactive compounds revealed the importance of positive and negative electrostatic patterns of phenyl aminoethanol derivatives. Time-of-addition experiments and visualization of the intracellular localization of nucleoprotein NP demonstrated that an early step of the virus life cycle was suppressed by nylidrin. Ultimately, we discovered that nylidrin targets hemagglutinin 2 (HA2)-mediated membrane fusion by blocking conformational change of HA at acidic pH. In a mouse model, preincubation of a mouse-adapted influenza A virus (H1N1) with nylidrin completely blocked intranasal viral infection. The present study suggests that nylidrin could provide a core chemical skeleton for the development of a direct-acting inhibitor of influenza A virus entry.


Assuntos
Antivirais/farmacologia , Hemaglutininas/efeitos dos fármacos , Vírus da Influenza A/efeitos dos fármacos , Fusão de Membrana/efeitos dos fármacos , Nilidrina/farmacologia , Células A549 , Animais , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Nucleoproteínas/metabolismo , Nilidrina/análogos & derivados , Internalização do Vírus/efeitos dos fármacos
8.
Sci Rep ; 9(1): 5124, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30914762

RESUMO

The North Korean nuclear explosion test site in Punggye-ri is located in a seismically quiescent region on a stable Precambrian basement. The 3 September 2017 MW5.6 North Korean underground nuclear explosion (UNE) test produced unprecedented strong ground motions. The peak ground accelerations might reach tens to hundreds m/s2 on the surface of the UNE test site, decaying exponentially with distance. Ten shallow events with magnitudes greater than or equal to ML2.5 and source depths less than 3 km followed the 2017 UNE for 5 months in an area with a radius of 15 km from the UNE where strong ground shaking was experienced. The largest event with MW3.7 occurred 20 days after the 2017 UNE test at shallow depths less than 3 km. Its moment tensor solution indicates a combined source behavior with comparable strengths of double-couple and compensated linear vector dipole (CLVD) components, suggesting an unusual event different from typical natural earthquakes in the Korean Peninsula. The clustered shallow seismic events appeared to have occurred in damaged media that were effectively perturbed by the strong ground motions of the UNE.

9.
J Virol ; 92(24)2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30282713

RESUMO

Screening of chemical libraries with 2,000 synthetic compounds identified salinomycin as a hit against influenza A and B viruses, with 50% effective concentrations ranging from 0.4 to 4.3 µM in cells. This compound is a carboxylic polyether ionophore that exchanges monovalent ions for protons across lipid bilayer membranes. Monitoring the time course of viral infection showed that salinomycin blocked nuclear migration of viral nuclear protein (NP), the most abundant component of the viral ribonucleoprotein (vRNP) complex. It caused cytoplasmic accumulation of NP, particularly within perinuclear endosomes, during virus entry. This was primarily associated with failure to acidify the endosomal-lysosomal compartments. Similar to the case with amantadine (AMT), proton channel activity of viral matrix protein 2 (M2) was blocked by salinomycin. Using purified retroviral Gag-based virus-like particles (VLPs) with M2, it was proved that salinomycin directly affects the kinetics of a proton influx into the particles but in a manner different from that of AMT. Notably, oral administration of salinomycin together with the neuraminidase inhibitor oseltamivir phosphate (OSV-P) led to enhanced antiviral effect over that with either compound used alone in influenza A virus-infected mouse models. These results provide a new paradigm for developing antivirals and their combination therapy that control both host and viral factors.IMPORTANCE Influenza virus is a main cause of viral respiratory infection in humans as well as animals, occasionally with high mortality. Circulation of influenza viruses resistant to the matrix protein 2 (M2) inhibitor, amantadine, is highly prevalent. Moreover, the frequency of detection of viruses resistant to the neuraminidase inhibitors, including oseltamivir phosphate (OSV-P) or zanamivir, is also increasing. These issues highlight the need for discovery of new antiviral agents with different mechanisms. Salinomycin as the monovalent cation-proton antiporter exhibited consistent inhibitory effects against influenza A and B viruses. It plays multifunctional roles by blocking endosomal acidification and by inactivating the proton transport function of M2, the key steps for influenza virus uncoating. Notably, salinomycin resulted in marked therapeutic effects in influenza virus-infected mice when combined with OSV-P, suggesting that its chemical derivatives could be developed as an adjuvant antiviral therapy to treat influenza infections resistant or less sensitive to existing drugs.


Assuntos
Vírus da Influenza A/fisiologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Oseltamivir/administração & dosagem , Piranos/administração & dosagem , Proteínas da Matriz Viral/metabolismo , Administração Oral , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Proteínas do Nucleocapsídeo , Infecções por Orthomyxoviridae/virologia , Oseltamivir/farmacologia , Transporte Proteico/efeitos dos fármacos , Piranos/farmacologia , Proteínas de Ligação a RNA/metabolismo , Proteínas do Core Viral/metabolismo , Internalização do Vírus
10.
Bioorg Med Chem Lett ; 28(23-24): 3784-3786, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30301674

RESUMO

First-line medical treatment against nerve agents consists of co-administration of anticholinergic agents and oxime reactivators, which reactivate inhibited AChE. Pralidoxime, a commonly used oxime reactivator, is effective against some nerve agents but not against others; thus, new oxime reactivators are needed. Novel tacrine-pyridinium hybrid reactivators in which 4-pyridinealdoxime derivatives are connected to tacrine moieties by linear carbon chains of different lengths (C2-C7) were prepared (Scheme 1, 5a-f). Their binding affinities to electric eel AChE were tested because oximes can inhibit free AChE, and the highest AChE activity (95%, 92%, and 90%) was observed at 1 µM concentrations of the oximes (5a, 5b, and 5c, respectively). Based on their inhibitory affinities towards free AChE, 1 µM concentrations of the oxime derivatives (5) were used to examine reactivation of paraoxon-inhibited AChE. Reactivation ability increased as the carbon linker chains lengthened (n = 2-5), and 5c and 5d showed remarkable reactivation ability (41%) compared to that of 2-PAM (16%) and HI-6 (4%) against paraoxon-inhibited electric eel AChE at 1 µM concentrations. Molecular docking simulation showed that the most stable binding free energy was observed in 5c at 73.79 kcal⋅mol-1, and the binding mode of 5c is acceptable for the oxygen atom of oximate to attack the phosphorus atom of paraoxon and reactivate paraoxon-inhibited eel AChE model structure.


Assuntos
Acetilcolinesterase/metabolismo , Reativadores da Colinesterase/química , Reativadores da Colinesterase/farmacologia , Compostos de Piridínio/química , Compostos de Piridínio/farmacologia , Tacrina/química , Tacrina/farmacologia , Animais , Inibidores da Colinesterase/farmacologia , Reativadores da Colinesterase/síntese química , Electrophorus , Simulação de Acoplamento Molecular , Paraoxon/farmacologia , Compostos de Piridínio/síntese química , Tacrina/síntese química
12.
ACS Med Chem Lett ; 9(7): 667-672, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30034598

RESUMO

The human rhinovirus (hRV) is the causative agent of the common cold that often aggravates respiratory complications in patients with asthma or chronic obstructive pulmonary disease. The high rate of mutations and variety of serotypes are limiting the development of anti-hRV drugs, which emphasizes the need for the discovery of novel lead compounds. Previously, we identified antiviral compound 1 that we used here as the starting material for developing a novel compound series with high efficacy against hRV-A and -B. Improved metabolic stability was achieved by substituting an ester moiety with a 1,2,4-oxadiazole group. Specifically, compound 3k exhibited a high efficacy against hRV-B14, hRV-A21, and hRV-A71, with EC50 values of 66.0, 22.0, and 3.7 nM, respectively, and a relevant hepatic stability (59.6 and 40.7% compound remaining after 30 min in rat and human liver microsomes, respectively). An in vivo study demonstrated that 3k possessed a desirable pharmacokinetic profile with low systemic clearance (0.158 L·h-1·kg-1) and modest oral bioavailability (27.8%). Hence, 3k appears to be an interesting candidate for the development of antiviral lead compounds.

13.
Viruses ; 10(6)2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29795047

RESUMO

The Middle East respiratory syndrome-coronavirus (MERS-CoV), first identified in Saudi Arabia, is an emerging zoonotic pathogen that causes severe acute respiratory illness in humans with a high fatality rate. Since its emergence, MERS-CoV continues to spread to countries outside of the Arabian Peninsula and gives rise to sporadic human infections following the entry of infected individuals to other countries, which can precipitate outbreaks similar to the one that occurred in South Korea in 2015. Current therapeutics against MERS-CoV infection have primarily been adapted from previous drugs used for the treatment of severe acute respiratory syndrome. In search of new potential drug candidates, we screened a library composed of 2334 clinically approved drugs and pharmacologically active compounds. The drug saracatinib, a potent inhibitor of Src-family of tyrosine kinases (SFK), was identified as an inhibitor of MERS-CoV replication in vitro. Our results suggest that saracatinib potently inhibits MERS-CoV at the early stages of the viral life cycle in Huh-7 cells, possibly through the suppression of SFK signaling pathways. Furthermore, saracatinib exhibited a synergistic effect with gemcitabine, an anticancer drug with antiviral activity against several RNA viruses. These data indicate that saracatinib alone or in combination with gemcitabine can provide a new therapeutic option for the treatment of MERS-CoV infection.


Assuntos
Antivirais/farmacologia , Benzodioxóis/farmacologia , Inibidores Enzimáticos/farmacologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Quinazolinas/farmacologia , Replicação Viral/efeitos dos fármacos , Linhagem Celular , Infecção Hospitalar , Replicação do DNA , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Descoberta de Drogas , Humanos , Bibliotecas de Moléculas Pequenas , Quinases da Família src/antagonistas & inibidores
14.
Nucleic Acids Res ; 46(4): 1635-1647, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29373735

RESUMO

Retinoic acid-inducible gene I (RIG-I) recognizes double-stranded viral RNAs (dsRNAs) containing two or three 5' phosphates. A few reports of 5'-PPP-independent RIG-I agonists have emerged, but little is known about the molecular principles underlying their recognition. We recently found that the bent duplex RNA from the influenza A panhandle promoter activates RIG-I even in the absence of a 5'-triphosphate moiety. Here, we report that non-canonical synthetic RNA oligonucleotides containing G-U wobble base pairs that form a bent helix can exert RIG-I-mediated antiviral and anti-tumor effects in a sequence- and site-dependent manner. We present synthetic RNAs that have been systematically modified to enhance their efficacy and we outline the basic principles for engineering RIG-I agonists applicable to immunotherapy.

15.
J Microbiol ; 55(12): 979-983, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29214495

RESUMO

Influenza viruses are major human respiratory pathogens that cause high morbidity and mortality worldwide. Currently, prophylactic vaccines and therapeutic antiviral agents are used to prevent and control influenza virus infection. Oseltamivir free base (OSV-FB), a modified generic antiviral drug of Tamiflu (oseltamivir phosphate, OSV-P), was launched in the Republic of Korea last year. Here, we examine the bioequivalence of these two compounds by assessing their antiviral efficacy in infected cells and in a mouse model. It was observed that both antivirals showed comparable efficacy against 11 different influenza A and B viruses in vitro. Moreover, in mice infected with influenza A virus (mouse-adapted A/Puerto Rico/8/34), they showed a dose-dependent therapeutic activity and alleviated infection-mediated reductions in body weight, leading to significantly better survival. There was histopathological disappearance of virus-induced inflammatory cell infiltration of the lung after oral treatment with either antiviral agent (at 10 mg/kg). Pharmacokinetic analysis also exhibited similar plasma concentrations of the active drug, oseltamivir carboxylate, metabolised from both OSV-B and OSV-P. This is the first report showing bioequivalence of OSV-FB to its phosphate salt form in the mouse system. The free base drug has some beneficial points including simple drug formulation process and reduced risk of undesirable cation-phosphate precipitation within solution. The long term stability of OSV-FB requires further monitoring when it is provided as a national stock in readiness for an influenza pandemic.


Assuntos
Antivirais/administração & dosagem , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Oseltamivir/análogos & derivados , Oseltamivir/administração & dosagem , Animais , Antivirais/farmacocinética , Feminino , Humanos , Vírus da Influenza A/fisiologia , Vírus da Influenza B/fisiologia , Influenza Humana/virologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Oseltamivir/farmacocinética , Equivalência Terapêutica
16.
J Med Chem ; 60(13): 5472-5492, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28581749

RESUMO

Human rhinoviruses (hRVs) are the main causative pathogen for common colds and are associated with the exacerbation of asthma. The wide variety in hRV serotypes has complicated the development of rhinovirus replication inhibitors. In the current investigation, we developed a novel series of benzothiophene derivatives and their analogues (6-8) that potently inhibit the replication of both hRV-A and hRV-B strains. Compound 6g inhibited the replication of hRV-B14, A21, and A71, with respective EC50 values of 0.083, 0.078, and 0.015 µM. The results of a time-of-addition study against hRV-B14 and hRV-A16 and resistant mutation analysis on hRV-B14 implied that 6g acts at the early stage of the viral replication process, interacting with viral capsid protein. A molecular docking study suggested that 6g has a capsid-binding mode similar to that of pleconaril. Finally, derivatives of 6 also displayed significant inhibition against poliovirus 3 (PV3) replication, implying their potential inhibitory activities against other enterovirus species.


Assuntos
Antivirais/farmacologia , Rhinovirus/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Tiofenos/farmacologia , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Replicação Viral/efeitos dos fármacos
17.
Antiviral Res ; 141: 101-106, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28216367

RESUMO

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe acute respiratory illness with fever, cough and shortness of breath. Up to date, it has resulted in 1826 human infections, including 649 deaths. Analogous to picornavirus 3C protease (3Cpro), 3C-like protease (3CLpro) is critical for initiation of the MERS-CoV replication cycle and is thus regarded as a validated drug target. As presented here, our peptidomimetic inhibitors of enterovirus 3Cpro (6b, 6c and 6d) inhibited 3CLpro of MERS-CoV and severe acute respiratory syndrome coronavirus (SARS-CoV) with IC50 values ranging from 1.7 to 4.7 µM and from 0.2 to 0.7 µM, respectively. In MERS-CoV-infected cells, the inhibitors showed antiviral activity with EC50 values ranging from 0.6 to 1.4 µM, by downregulating the viral protein production in cells as well as reducing secretion of infectious viral particles into culture supernatants. They also suppressed other α- and ß-CoVs from human and feline origin. These compounds exhibited good selectivity index (over 70 against MERS-CoV) and could lead to the development of broad-spectrum antiviral drugs against emerging CoVs and picornaviruses.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/isolamento & purificação , Gatos , Coronavirus/efeitos dos fármacos , Infecções por Coronavirus/virologia , Humanos , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Inibidores de Proteases/farmacologia , Vírus da SARS/efeitos dos fármacos , Proteínas Virais
18.
Antiviral Res ; 134: 77-88, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27565992

RESUMO

The spiro compound 5,6-dimethyl-3H,3'H-spiro(benzofuran-2,1'-isobenzofuran)-3,3'-dione (KR-23502) has antiviral activity against influenza A and more potently B viruses. The aim of this study is to elucidate its mechanism of action. Subcellular localization and time-course expression of influenza B viral proteins, nucleoprotein (NP) and matrix protein 1 (M1), showed that KR-23502 reduced their amounts within 5 h post-infection. Early steps of virus life cycle, including virus entry, nuclear localization of NP and viral RNA-dependent RNA replication, were not affected by KR-23502. Instead it interrupted a later event corresponding to nuclear export of NP and M1 proteins. Delivery of viral ribonucleoprotein (vRNP)-M1 complex has been known to be mediated by the viral nuclear export protein (NEP) through interaction with cellular chromosomal maintenance 1 (CRM1) protein. In this study, we experimentally demonstrated that the compound targets the nuclear export of vRNP. Moreover, a single mutation (aspartate to glycine) at amino acid position 54 in M1 [M1(D54G)] was detected after 18 passages in the presence of KR-23502 with a 2-fold increase in 50% effective concentration indicating that this compound has a relatively high genetic barrier to resistance. Interestingly, it was observed that proteasome-mediated degradation of M1(D54G) was attenuated by KR-23502. In conclusion, we suggest that KR-23502 shows its anti-influenza activity by downregulating NEP/CRM1-mediated nuclear export of influenza vRNP and M1. KR-23502 provides a core chemical skeleton for further structure-based design of novel antivirals against influenza viruses.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Antivirais/farmacologia , Benzofuranos/farmacologia , Vírus da Influenza B/efeitos dos fármacos , Ribonucleoproteínas/efeitos dos fármacos , Proteínas da Matriz Viral , Núcleo Celular/metabolismo , Humanos , Vírus da Influenza B/química , Vírus da Influenza B/genética , Influenza Humana/tratamento farmacológico , Mutação , RNA Viral , Ribonucleoproteínas/química , Ribonucleoproteínas/genética , Proteínas da Matriz Viral/efeitos dos fármacos , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacos
19.
Virol J ; 13: 99, 2016 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-27296985

RESUMO

BACKGROUND: Enterovirus 71 (EV71) is a major causative agent of hand-foot-mouth disease (HFMD) and also causes severe neurological complications, leading to fatality in young children. However, no effective therapy is currently available for the treatment of this infection. METHODS: We identified small-molecule inhibitors of EV71 from a screen of 968 Food and Drug Administration (FDA)-approved drugs, with which clinical application for EV71-associated diseases would be more feasible, using EV71 subgenomic replicon system. Primary hits were extensively evaluated for their antiviral activities in EV71-infected cells. RESULTS: We identified micafungin, an echinocandin antifungal drug, as a novel inhibitor of EV71. Micafungin potently inhibits the proliferation of EV71 as well as the replication of EV71 replicon in cells with a low micromolar IC50 (~5 µM). The strong antiviral effect of micafungin on EV71 replicon and the result from time-of-addition experiment demonstrated a targeting of micafungin on virion-independent intracellular process(es) during EV71 infection. Moreover, an extensive analysis excluded the involvement of 2C and 3A proteins, IRES-dependent translation, and also that of polyprotein processing in the antiviral effect of micafungin. CONCLUSIONS: Our research revealed a new indication of micafungin as an effective inhibitor of EV71, which is the first case reporting antiviral activity of micafungin, an antifungal drug.


Assuntos
Antivirais/farmacologia , Equinocandinas/farmacologia , Enterovirus Humano A/efeitos dos fármacos , Lipopeptídeos/farmacologia , Animais , Linhagem Celular , Reposicionamento de Medicamentos , Humanos , Micafungina
20.
Opt Express ; 24(6): 5709-14, 2016 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-27136768

RESUMO

Optical wavelength filters with large tuning range and narrow bandwidth are crucial for enhancing the capability of WDM communication systems. A polymeric tunable filter for C-band, comprising a tilted Bragg grating and a mode sorting waveguide junction is proposed in this work. For dropping a certain wavelength signal, the tilted Bragg grating reflects an odd mode into an even mode and then the reflected even mode propagates towards an output port of the asymmetric Y-junction due to the mode sorting. Consequently, the output port is separated from the input port, which is not possible in an ordinary Bragg reflector. The tilted Bragg reflector with an odd-even mode coupling efficiency of 61% exhibited a maximum reflectivity of 95% for a grating of 6 mm. A linear wavelength tuning of over 10 nm was achieved for an applied thermal power of 312 mW.

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