Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.601
Filtrar
1.
J Med Virol ; 94(1): 161-172, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34415583

RESUMO

Detailed information on intrahost viral evolution in SARS-CoV-2 with and without treatment is limited. Sequential viral loads and deep sequencing of SARS-CoV-2 from the upper respiratory tract of nine hospitalized children, three of whom were treated with remdesivir, revealed that remdesivir treatment suppressed viral load in one patient but not in a second infected with an identical strain without any evidence of drug resistance found. Reduced levels of subgenomic RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication. Haplotype reconstruction uncovered persistent SARS-CoV-2 variant genotypes in four patients. These likely arose from within-host evolution, although superinfection cannot be excluded in one case. Although our dataset is small, observed sample-to-sample heterogeneity in variant frequencies across four of nine patients suggests the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalization could compromise the penetration of remdesivir into the lung, limiting the drugs in vivo efficacy, as has been observed in other lung infections.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/virologia , Evolução Molecular , SARS-CoV-2/genética , Monofosfato de Adenosina/uso terapêutico , Adolescente , Alanina/uso terapêutico , Criança , Pré-Escolar , Farmacorresistência Viral , Feminino , Haplótipos , Humanos , Lactente , Pulmão/virologia , Masculino , Filogenia , RNA Viral/análise , RNA Viral/genética , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Carga Viral , Replicação Viral/efeitos dos fármacos
2.
J Med Virol ; 94(1): 384-387, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34406670

RESUMO

The antiviral remdesivir has been shown to decrease the length of hospital stay in coronavirus disease 2019 (COVID-19) patients requiring supplemental oxygen. However many patients decompensate despite being treated with remdesivir. To identify potential prognostic factors in remdesivir-treated patients, we performed a retrospective cohort study of patients hospitalized at NewYork-Presbyterian Hospital/Weill Cornell Medical Center between March 23, 2020 and May 27, 2020. We identified 55 patients who were treated with remdesivir for COVID-19 and analyzed inflammatory markers and clinical outcomes. C-reactive protein (CRP), d-dimer, and lactate dehydrogenase levels were significantly higher in patients who progressed to intubation or death by 14 days compared to those who remained stable. CRP levels decreased significantly after remdesivir administration in patients who remained nonintubated over the study period. To our knowledge, this is the largest study to date examining inflammatory markers before and after remdesivir administration. Our findings support further investigation into COVID-19 treatment strategies that modify the inflammatory response.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/mortalidade , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/uso terapêutico , Idoso , Alanina/uso terapêutico , Biomarcadores/sangue , Proteína C-Reativa/análise , COVID-19/patologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Inflamação/tratamento farmacológico , L-Lactato Desidrogenase/sangue , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , SARS-CoV-2/imunologia
3.
Cad Saude Publica ; 37(10): e00077721, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34787281

RESUMO

The U.S. Food and Drug Administration (FDA) has stated that the prescription of remdesivir should be cautious for patients with estimated glomerular filtration rate (eGFR) < 30 and some studies reported risk of adverse renal events. The available information on the renal safety profile for remdesivir is limited, thus we analyzed the renal and urinary adverse reactions attributed to remdesivir reported in a large open pharmacovigilance database. We obtained reports of remdesivir and other drugs used to treat COVID-19 (tocilizumab, hydroxychloroquine, lopinavir/ritonavir) registered by September 30 2020, from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed the reporting odds ratios (RORs) for reports of adverse renal and urinary events for remdesivir and other drugs. We found 2,922 reports with remdesivir registered in FAERS for COVID-19. Among these, 493 renal and urinary adverse effects (16.9%) were reported. The most frequent events were acute kidney injury (338; 11.6%), renal impairment (86; 2.9%), and renal failure (53; 1.8%). Versus hydroxychloroquine, lopinavir/ritonavir, or tocilizumab, the use of remdesivir was associated with an increased chance of reporting renal and urinary disorders regardless of gender and age of patients (2.53; 95%CI: 2.10-3.06). The ROR remained significant when we restricted the analysis to hydroxychloroquine (4.31; 95%CI: 3.25-5.71) or tocilizumab (3.92; 95%CI: 2.51-6.12). Our results reinforce this already reported signal, emphasizing that it could be extremely useful for health professionals who prescribe this new antiviral to treat COVID-19, mainly knowing its low efficacy.


Assuntos
COVID-19 , Farmacovigilância , Monofosfato de Adenosina/análogos & derivados , Sistemas de Notificação de Reações Adversas a Medicamentos , Alanina/análogos & derivados , Brasil , COVID-19/tratamento farmacológico , Humanos , Rim , SARS-CoV-2
4.
Toxicol Appl Pharmacol ; 433: 115783, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34740633

RESUMO

Remdesivir is one of a few antiviral drugs approved for treating severe cases of coronavirus 2 (SARS-CoV-2) infection in hospitalized patients. The prodrug is a nucleoside analog that interferes with viral replication by inhibiting viral RNA-dependent RNA polymerase. The drug has also been shown to be a weak inhibitor of human mitochondrial RNA polymerase, leaving open the possibility of mitochondrial off-targets and toxicity. The investigation was designed to explore whether remdesivir causes mitochondrial toxicity, using both genomic and functional parameters in the assessment. Human-derived HepG2 liver cells were exposed for up to 48 h in culture to increasing concentrations of remdesivir. At sub-cytotoxic concentrations (<1 µM), the drug failed to alter either the number of copies or the expression of the mitochondrial genome. mtDNA copy number was unaffected as was the relative rates of expression of mtDNA-encoded and nuclear encoded subunits of complexes I and IV of the mitochondrial respiratory chain. Consistent with this is the observation that remdesivir was without effect on mitochondrial respiration, including basal respiration, proton leak, maximum uncoupled respiration, spare respiratory capacity or coupling efficiency. We conclude that although remdesivir has weak inhibitory activity towards mitochondrial RNA polymerase, mitochondria are not primary off-targets for the mechanism of cytotoxicity of the drug.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/farmacologia , COVID-19/metabolismo , DNA Mitocondrial/antagonistas & inibidores , DNA Mitocondrial/metabolismo , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , RNA Polimerases Dirigidas por DNA/metabolismo , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo
5.
Trials ; 22(1): 831, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34814933

RESUMO

BACKGROUND: Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. METHODS: This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion. DISCUSSION: This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. TRIAL REGISTRATION: ClinicalTrials.gov NCT04385719 . Registered 13 May 2020.


Assuntos
Fármacos Anti-HIV , Lamivudina , Monofosfato de Adenosina/análogos & derivados , Adulto , Alanina/análogos & derivados , Sulfato de Atazanavir , Voluntários Saudáveis , Humanos , Oligopeptídeos , Piridinas , Ritonavir , Tenofovir , Uganda
6.
Farm Hosp ; 45(5): 253-257, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34806585

RESUMO

OBJECTIVE: To describe the effectiveness and safety of remdesivir in patients with SARS-CoV-2 pneumonia in real-world clinical practice  conditions. METHOD: Retrospective observational study that included all adults with  SARS-CoV-2 pneumonia admitted at the Moisès Broggi Hospital and  treated with remdesivir between July 1st and November 7th, 2020.  Efficacy outcomes were time to recovery, 28-day mortality, length of  hospital stay, and the need of mechanical ventilation after treatment. The  main safetyrelated endpoint was elevation of transaminases after  treatment. RESULTS: A total of 111 patients were included of whom 97 (87.4%) were receiving low-flow oxygen therapy. Median time to recovery was 9  days [6-14]. Seven patients (6.3%) died at 28 days' follow-up. Median  length of hospital stay was 12 days [9-22] and 15 patients (13.5%)  needed mechanical ventilation after treatment with remdesivir. Severe  hypertransaminasemia was observed in 4 patients (4%). CONCLUSIONS: Clinical outcomes of patients with SARS-CoV-2 pneumonia on low-flow oxygen therapy treated with remdesivir were  similar to those published in clinical trials, both in terms of time to  recovery and 28-day mortality.


Assuntos
COVID-19 , SARS-CoV-2 , Monofosfato de Adenosina/análogos & derivados , Adulto , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Humanos , Resultado do Tratamento
7.
Pak J Pharm Sci ; 34(3(Supplementary)): 1119-1126, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34602441

RESUMO

The pandemic Coronavirus (Covid-19) is continuously growing and spreading at the highest rate in all over the world. So, it is necessary to produce the new medicinal agents against this virus. The aim of the present study is to design a potent compound against COVID-19. Based on 3C-like main protease and recently developed solved structure (PDB ID: 6Y2F), a series of remdesivir analogs are designed and analyzed by employing molecular modeling against the SARS-CoV-2 by insilico approach. The molecular dynamics (MD) simulation for 500ps was performed to check the stability and orientation to inside the binding pocket for analogs R3, R9, R14 and R15. The study results exhibit that compsound R9 has strong interaction or least binding energy (-10.04kcal/mol) as compare to the other analogues due to the presences of methyl bromide and it may be useful to further investigation in vitro testing against Covid-19.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Peptídeo Hidrolases/metabolismo , Inibidores de Proteases/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/uso terapêutico , Alanina/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Pandemias/prevenção & controle , SARS-CoV-2/metabolismo , Proteínas não Estruturais Virais/metabolismo
8.
Sci Rep ; 11(1): 19458, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593911

RESUMO

Efficacious therapeutics for Ebola virus disease are in great demand. Ebola virus infections mediated by mucosal exposure, and aerosolization in particular, present a novel challenge due to nontypical massive early infection of respiratory lymphoid tissues. We performed a randomized and blinded study to compare outcomes from vehicle-treated and remdesivir-treated rhesus monkeys in a lethal model of infection resulting from aerosolized Ebola virus exposure. Remdesivir treatment initiated 4 days after exposure was associated with a significant survival benefit, significant reduction in serum viral titer, and improvements in clinical pathology biomarker levels and lung histology compared to vehicle treatment. These observations indicate that remdesivir may have value in countering aerosol-induced Ebola virus disease.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Ebolavirus/efeitos dos fármacos , Doença pelo Vírus Ebola/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Administração Intravenosa , Aerossóis , Alanina/administração & dosagem , Alanina/farmacologia , Animais , Antivirais/administração & dosagem , Modelos Animais de Doenças , Feminino , Doença pelo Vírus Ebola/sangue , Estimativa de Kaplan-Meier , Fígado/efeitos dos fármacos , Fígado/virologia , Pulmão/patologia , Pulmão/virologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Linfonodos/virologia , Macaca mulatta , Masculino , Distribuição Aleatória , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/virologia , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico
9.
Nat Commun ; 12(1): 5809, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34608167

RESUMO

SARS-CoV-2 has caused a global pandemic of COVID-19 since its emergence in December 2019. The infection causes a severe acute respiratory syndrome and may also spread to central nervous system leading to neurological sequelae. We have developed and characterized two new organotypic cultures from hamster brainstem and lung tissues that offer a unique opportunity to study the early steps of viral infection and screening antivirals. These models are not dedicated to investigate how the virus reaches the brain. However, they allow validating the early tropism of the virus in the lungs and demonstrating that SARS-CoV-2 could infect the brainstem and the cerebellum, mainly by targeting granular neurons. Viral infection induces specific interferon and innate immune responses with patterns specific to each organ, along with cell death by apoptosis, necroptosis, and pyroptosis. Overall, our data illustrate the potential of rapid modeling of complex tissue-level interactions during infection by a newly emerged virus.


Assuntos
Tronco Encefálico/virologia , Pulmão/virologia , Modelos Biológicos , SARS-CoV-2/patogenicidade , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Células Epiteliais Alveolares/virologia , Animais , Antivirais/farmacologia , Tronco Encefálico/citologia , Tronco Encefálico/imunologia , Tronco Encefálico/patologia , Cricetinae , Imunidade Inata , Inflamação , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Neurônios/virologia , Técnicas de Cultura de Órgãos , Morte Celular Regulada , SARS-CoV-2/efeitos dos fármacos , Tropismo Viral
11.
J Hematol Oncol ; 14(1): 163, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635137

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently constitutes the leading and overwhelming health issue worldwide. In comparison with adults, children present milder symptoms, with most having an asymptomatic course. We hypothesized that COVID-19 infection has a negative impact on the continuation of chemotherapy and increases nonrelapse mortality. MATERIAL AND METHODS: This study was performed to assess the course of SARS-CoV-2 among children with hematological or oncological malignancies and its impact on cancer therapy. Records of SARS-CoV-2 infection in 155 children with malignancies from 14 Polish centers for pediatric hematology and oncology were collected and analyzed. RESULTS: SARS-CoV-2 replication was observed in 155 patients. Forty-nine patients were symptomatic, with the following being the most common manifestations: fever (31 patients), gastrointestinal symptoms (10), coryza (13), cough (13) and headache (8). In children who were retested, the median time of a positive PCR result was 16 days (range 1-70 days), but 12.7% of patients were positive beyond day + 20. The length of viral PCR positivity correlated with the absolute neutrophil count at diagnosis. Seventy-six patients did not undergo further SARS-CoV-2 testing and were considered convalescents after completion of isolation. Antibiotic therapy was administered in 15 children, remdesivir in 6, convalescent plasma in 4, oxygen therapy in 3 (1-mechanical ventilation), steroids in 2, intravenous immunoglobulins in 2, and heparin in 4. Eighty patients were treated with chemotherapy within 30 days after SARS-CoV-2 infection diagnosis or were diagnosed with SARS-CoV-2 infection during 30 days of chemotherapy administration. Respiratory symptoms associated with COVID-19 and associated with oxygen therapy were present in 4 patients in the study population, and four deaths were recorded (2 due to COVID-19 and 2 due to progressive malignancy). The probability of 100-day overall survival was 97.3% (95% CI 92.9-99%). Delay in the next chemotherapy cycle occurred in 91 of 156 cases, with a median of 14 days (range 2-105 days). CONCLUSIONS: For the majority of pediatric cancer patients, SARS-CoV-2 infection does not result in a severe, life-threatening course. Our data show that interruptions in therapy are common and can result in suboptimal therapy.


Assuntos
COVID-19/complicações , COVID-19/terapia , Neoplasias Hematológicas/complicações , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Adolescente , Alanina/análogos & derivados , Alanina/uso terapêutico , Antivirais/uso terapêutico , COVID-19/diagnóstico , COVID-19/epidemiologia , Criança , Pré-Escolar , Gerenciamento Clínico , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Imunização Passiva , Lactente , Masculino , Polônia/epidemiologia , SARS-CoV-2/isolamento & purificação
12.
Medicine (Baltimore) ; 100(37): e27228, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34664862

RESUMO

ABSTRACT: Remdesivir is the only antiviral approved for lower respiratory tract infection produced by SARS-CoV-2. The main objective of this study was to determine the mortality rate, readmissions, mean hospital stay, need for higher levels of oxygen support, and adverse effect-induced abandonment rate in hospitalized patients diagnosed with COVID-19 and treated with remdesivir (RDSV). The secondary objective was to determine mortality-related risk factors in these patients.The study included a prospective cohort of patients admitted to a third level Spanish hospital between July 5, 2020 and February 3, 2021 for COVID-19 diagnosed by SARS-CoV-2 polymerase chain reaction and/or antigen test and treated with RDSV.Remdesivir was received by 185 patients (69.7% males) with a mean age of 62.5 years, median Charlson index of 3 (interquartile range [IQR]: 1-4), and median ambient air oxygen saturation of 91% (IQR: 90-93); 61.6% of patients had hyper-inflammatory syndrome at admission. Median time with symptoms before RDSV treatment was 5 days (IQR: 3-6) and the median hospital stay was 10 days (IQR: 7-15); 19 patients (10.3%) died after a median stay of 13.5 days (IQR: 9.7-24 days), 58 patients (12.9%) were admitted to ICU, 58 (31.4%) needed higher levels of oxygen support, 0.5% abandoned the treatment due to adverse effects, and there were no readmissions. The only mortality-related factor was the need for higher levels of oxygen support (odds ratio 12.02; 95% confidence interval 2.25-64.2).All studied patients were admitted to hospital with a diagnosis of COVID-19 and in respiratory failure, needing initial low-flow oxygen support, and all received RDSV within 1 week of symptom onset. The percent mortality was lower in these patients than was observed in all patients with severe COVID-19 admitted to our center (10.3% vs 20.3%, respectively). Despite receiving RDSV, 1 in 3 patients needed higher levels of oxygen support, the sole mortality-related factor.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , COVID-19/tratamento farmacológico , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Idoso , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/complicações , COVID-19/mortalidade , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Estudos Retrospectivos , Espanha , Estatísticas não Paramétricas
13.
Enzymes ; 49: 39-62, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34696838

RESUMO

Nucleotide analogs are the cornerstone of direct acting antivirals used to control infection by RNA viruses. Here we review what is known about existing nucleotide/nucleoside analogs and the kinetics and mechanisms of RNA and DNA replication, with emphasis on the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) in comparison to HIV reverse transcriptase and Hepatitis C RdRp. We demonstrate how accurate kinetic analysis reveals surprising results to explain the effectiveness of antiviral nucleoside analogs providing guidelines for the design of new inhibitors.


Assuntos
COVID-19 , Hepatite C Crônica , Monofosfato de Adenosina , Alanina , Antivirais/farmacologia , Humanos , Cinética , Nucleotídeos , RNA Viral/genética , SARS-CoV-2
15.
Mol Med Rep ; 24(6)2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34664677

RESUMO

The spread of the novel severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) emerged suddenly at the end of 2019 and the disease came to be known as coronavirus disease 2019 (COVID­19). To date, there is no specific therapy established to treat COVID­19. Identifying effective treatments is urgently required to treat patients and stop the transmission of SARS­CoV­2 in humans. For the present review, >100 publications on therapeutic agents for COVID­19, including in vitro and in vivo animal studies, case reports, retrospective analyses and meta­analyses were retrieved from PubMed and analyzed, and promising therapeutic agents that may be used to combat SARS­CoV­2 infection were highlighted. Since the outbreak of COVID­19, different drugs have been repurposed for its treatment. Existing drugs, including chloroquine (CQ), its derivative hydroxychloroquine (HCQ), remdesivir and nucleoside analogues, monoclonal antibodies, convalescent plasma, Chinese herbal medicine and natural compounds for treating COVID­19 evaluated in experimental and clinical studies were discussed. Although early clinical studies suggested that CQ/HCQ produces antiviral action, later research indicated certain controversy regarding their use for treating COVID­19. The molecular mechanisms of these therapeutic agents against SARS­CoV2 have been investigated, including inhibition of viral interactions with angiotensin­converting enzyme 2 receptors in human cells, viral RNA­dependent RNA polymerase, RNA replication and the packaging of viral particles. Potent therapeutic options were reviewed and future challenges to accelerate the development of novel therapeutic agents to treat and prevent COVID­19 were acknowledged.


Assuntos
COVID-19/terapia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Animais , Antimaláricos/uso terapêutico , Antivirais/uso terapêutico , COVID-19/diagnóstico , Cloroquina/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Imunização Passiva , SARS-CoV-2/isolamento & purificação
16.
Viruses ; 13(10)2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34696509

RESUMO

We report the in vitro efficacy of ion-channel inhibitors amantadine, memantine and rimantadine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In VeroE6 cells, rimantadine was most potent followed by memantine and amantadine (50% effective concentrations: 36, 80 and 116 µM, respectively). Rimantadine also showed the highest selectivity index, followed by amantadine and memantine (17.3, 12.2 and 7.6, respectively). Similar results were observed in human hepatoma Huh7.5 and lung carcinoma A549-hACE2 cells. Inhibitors interacted in a similar antagonistic manner with remdesivir and had a similar barrier to viral escape. Rimantadine acted mainly at the viral post-entry level and partially at the viral entry level. Based on these results, rimantadine showed the most promise for treatment of SARS-CoV-2.


Assuntos
Amantadina/farmacologia , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Memantina/farmacologia , Rimantadina/farmacologia , SARS-CoV-2/efeitos dos fármacos , Células A549 , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Linhagem Celular Tumoral , Chlorocebus aethiops , Dinamarca , Reposicionamento de Medicamentos , Humanos , Canais Iônicos/antagonistas & inibidores , Células Vero
17.
J Microbiol ; 59(11): 1056-1062, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34613605

RESUMO

The COVID-19 pandemic has caused unprecedented health, social, and economic crises worldwide. However, to date, there is an only a limited effective treatment for this disease. Human placenta hydrolysate (hPH) has previously been shown to be safe and to improve the health condition in patients with hyperferritinemia and COVID-19. In this study, we aimed to determine the antiviral effects of hPH against SARS-CoV-2 in vitro and in vivo models and compared with Remdesivir, an FDA-approved drug for COVID-19 treatment. To assess whether hPH inhibited SARS-CoV-2 replication, we determined the CC50, EC50, and selective index (SI) in Vero cells by infection with a SARS-CoV-2 at an MOI of 0.01. Further, groups of ferrets infected with 105.8 TCID50/ml of SARS-CoV-2 and treated with hPH at 2, 4, 6 dpi, and compared their clinical manifestation and virus titers in respiratory tracts with PBS control-treated group. The mRNA expression of immune-related cytokines was determined by qRT-PCR. hPH treatment attenuated virus replication in a dose-dependent manner in vitro. In a ferret infection study, treatment with hPH resulted in minimal bodyweight loss and attenuated virus replication in the nasal wash, turbinates, and lungs of infected ferrets. In addition, qRT-PCR results revealed that the hPH treatment remarkably upregulated the gene expression of type I (IFN-α and IFN-ß) and II (IFN-γ) IFNs in SARS-CoV-2 infected ferrets. Our data collectively suggest that hPH has antiviral efficacy against SARS-CoV-2 and might be a promising therapeutic agent for the treatment of SARS-CoV-2 infection.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Placenta/química , Hidrolisados de Proteína , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/farmacologia , Alanina/uso terapêutico , Animais , Chlorocebus aethiops , Feminino , Furões , Humanos , Masculino , Gravidez , Hidrolisados de Proteína/farmacologia , Hidrolisados de Proteína/uso terapêutico , Células Vero , Replicação Viral/efeitos dos fármacos
18.
Nat Commun ; 12(1): 6055, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663813

RESUMO

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.


Assuntos
COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/administração & dosagem , Indóis/administração & dosagem , Leucina/administração & dosagem , Pirrolidinonas/administração & dosagem , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacocinética , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/análogos & derivados , Alanina/farmacocinética , Animais , COVID-19/virologia , Chlorocebus aethiops , Coronavirus Humano 229E/efeitos dos fármacos , Coronavirus Humano 229E/enzimologia , Inibidores de Protease de Coronavírus/efeitos adversos , Inibidores de Protease de Coronavírus/farmacocinética , Modelos Animais de Doenças , Desenho de Fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Células HeLa , Humanos , Indóis/efeitos adversos , Indóis/farmacocinética , Infusões Intravenosas , Leucina/efeitos adversos , Leucina/farmacocinética , Camundongos , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/enzimologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Células Vero
19.
Mitochondrion ; 61: 147-158, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34619353

RESUMO

The COVID-19 pandemic prompted the FDA to authorize a new nucleoside analogue, remdesivir, for emergency use in affected individuals. We examined the effects of its active metabolite, remdesivir triphosphate (RTP), on the activity of the replicative mitochondrial DNA polymerase, Pol γ. We found that while RTP is not incorporated by Pol γ into a nascent DNA strand, it remains associated with the enzyme impeding its synthetic activity and stimulating exonucleolysis. In spite of that, we found no evidence for deleterious effects of remdesivir treatment on the integrity of the mitochondrial genome in human cells in culture.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , COVID-19/tratamento farmacológico , DNA Polimerase gama/metabolismo , Replicação do DNA/efeitos dos fármacos , DNA Mitocondrial/biossíntese , Fibroblastos/metabolismo , SARS-CoV-2 , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , COVID-19/metabolismo , Células Cultivadas , Humanos
20.
Elife ; 102021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34617885

RESUMO

The absence of 'shovel-ready' anti-coronavirus drugs during vaccine development has exceedingly worsened the SARS-CoV-2 pandemic. Furthermore, new vaccine-resistant variants and coronavirus outbreaks may occur in the near future, and we must be ready to face this possibility. However, efficient antiviral drugs are still lacking to this day, due to our poor understanding of the mode of incorporation and mechanism of action of nucleotides analogs that target the coronavirus polymerase to impair its essential activity. Here, we characterize the impact of remdesivir (RDV, the only FDA-approved anti-coronavirus drug) and other nucleotide analogs (NAs) on RNA synthesis by the coronavirus polymerase using a high-throughput, single-molecule, magnetic-tweezers platform. We reveal that the location of the modification in the ribose or in the base dictates the catalytic pathway(s) used for its incorporation. We show that RDV incorporation does not terminate viral RNA synthesis, but leads the polymerase into backtrack as far as 30 nt, which may appear as termination in traditional ensemble assays. SARS-CoV-2 is able to evade the endogenously synthesized product of the viperin antiviral protein, ddhCTP, though the polymerase incorporates this NA well. This experimental paradigm is essential to the discovery and development of therapeutics targeting viral polymerases.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , Nucleotídeos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Linhagem Celular , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Humanos , Modelos Teóricos , Nucleotídeos/metabolismo , RNA Viral , SARS-CoV-2/enzimologia , Processos Estocásticos , Replicação Viral/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...