RESUMO
Monkeypox (MPXV) is one of the infectious viruses which caused morbidity and mortality problems in these years. Despite its danger to public health, there is no approved drug to stand and handle MPXV. On the other hand, drug repurposing is a promising screening method for the low-cost introduction of approved drugs for emerging diseases and viruses which utilizes computational methods. Therefore, drug repurposing is a promising approach to suggesting approved drugs for the MPXV. This paper proposes a computational framework for MPXV antiviral prediction. To do this, we have generated a new virus-antiviral dataset. Moreover, we applied several machine learning and one deep learning method for virus-antiviral prediction. The suggested drugs by the learning methods have been investigated using docking studies. The target protein structure is modeled using homology modeling and, then, refined and validated. To the best of our knowledge, this work is the first work to study deep learning methods for the prediction of MPXV antivirals. The screening results confirm that Tilorone, Valacyclovir, Ribavirin, Favipiravir, and Baloxavir marboxil are effective drugs for MPXV treatment.
Assuntos
Antivirais , Aprendizado Profundo , Reposicionamento de Medicamentos , Monkeypox virus , Antivirais/farmacologia , Monkeypox virus/efeitos dos fármacos , Reposicionamento de Medicamentos/métodos , Pirazinas/farmacologia , Simulação de Acoplamento Molecular , Dibenzotiepinas , Amidas/farmacologia , Ribavirina/farmacologia , Triazinas/farmacologia , Mpox/tratamento farmacológico , Mpox/virologia , Humanos , Aprendizado de Máquina , Morfolinas , PiridonasRESUMO
Combining different drugs synergistically is an essential aspect of developing effective treatments. Although there is a plethora of research on computational prediction for new combination therapies, there is limited to no research on combination therapies in the treatment of viral diseases. This paper proposes AI-based models for predicting novel antiviral combinations to treat virus diseases synergistically. To do this, we assembled a comprehensive dataset comprising information on viral strains, drug compounds, and their known interactions. As far as we know, this is the first dataset and learning model on combination therapy for viruses. Our proposal includes using a random forest model, an SVM model, and a deep model to train viral combination therapy. The machine learning models showed the highest performance, and the predicted values were validated by a t-test, indicating the effectiveness of the proposed methods. One of the predicted combinations of acyclovir and ribavirin has been experimentally confirmed to have a synergistic antiviral effect against herpes simplex type-1 virus, as described in the literature.
Assuntos
Antivirais , Sinergismo Farmacológico , Quimioterapia Combinada , Aprendizado de Máquina , Antivirais/uso terapêutico , Antivirais/farmacologia , Humanos , Ribavirina/uso terapêutico , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Aciclovir/uso terapêutico , Aciclovir/administração & dosagem , Aciclovir/farmacologia , Viroses/tratamento farmacológicoRESUMO
BACKGROUND AND AIMS: Systematic reviews and medical guidelines are widely used in clinical practice. However, these are often not up-to-date and focussed on the average patient. We therefore aimed to evaluate a guideline add-on, TherapySelector (TS), which is based on monthly updated data of all available high-quality studies, classified in specific patient profiles. METHODS: We evaluated the TS for the treatment of hepatitis C (HCV) in an international cohort of patients treated with direct-acting antivirals between 2015 and 2020. The primary outcome was the number of patients receiving one of the two preferred treatment options of the HCV TS, based on the highest level of evidence, cure rate, absence of ribavirin-associated adverse effects, and treatment duration. RESULTS: We enrolled 567 patients. The number of patients treated with one of the two preferred treatment options according to the HCV TS ranged between 27% (2015) and 60% (2020; p < 0.001). Most of the patients received a regimen with a longer treatment-duration (up to 34%) and/or addition of ribavirin (up to 14%). The effect on the expected cure-rate was minimal (1-6% higher) when the first preferred TherapySelector option was given compared to the actual treatment. CONCLUSIONS: Medical decision-making can be optimised by a guideline add-on; in HCV its use appears to minimise adverse effects and cost. The use of such an add-on might have a greater impact in diseases with suboptimal cure-rates, high costs or adverse effects, for which treatment options rely on specific patient characteristics.
Assuntos
Antivirais , Guias de Prática Clínica como Assunto , Humanos , Antivirais/uso terapêutico , Guias de Prática Clínica como Assunto/normas , Feminino , Pessoa de Meia-Idade , Masculino , Hepatite C/tratamento farmacológico , Tomada de Decisão Clínica , Adulto , Idoso , Ribavirina/uso terapêutico , Hepatite C Crônica/tratamento farmacológicoRESUMO
Rabies is a fatal neurological disorder caused by rabies virus (RABV) infection. Approximately 60,000 patients die from rabies annually, and there are no effective treatments for this disease. Nucleoside analogs are employed as antiviral drugs based on their broad antiviral spectrum, and certain nucleoside analogs have been reported to exhibit anti-RABV activity. The nucleoside analog ß-d-N4-hydroxycytidine (NHC) has antiviral effects against a range of RNA viruses. Molnupiravir (MPV), a prodrug of NHC, is clinically used as an oral antiviral drug for coronavirus infections. Despite its broad-spectrum activity, the antiviral activity of NHC against RABV remains unclear. In this study, we reveal that NHC exhibits comparable in vitro anti-RABV activity as ribavirin and favipiravir (also known as T-705) with a 90% effective concentration of 6 µM in mouse neuroblastoma cells. NHC reduced viral loads in neuronal and nonneuronal cells in a dose-dependent manner. Both laboratory and field RABVs (fixed and street strains, respectively) were susceptible to NHC. However, no increase in survival or reduction in viral titers in the brain was observed in RABV-infected mice treated prophylactically with MPV. These findings highlight the potential and challenges of NHC in the treatment of RABV infection.
Assuntos
Amidas , Antivirais , Citidina , Vírus da Raiva , Raiva , Carga Viral , Animais , Antivirais/farmacologia , Citidina/análogos & derivados , Citidina/farmacologia , Vírus da Raiva/efeitos dos fármacos , Camundongos , Raiva/tratamento farmacológico , Raiva/virologia , Amidas/farmacologia , Carga Viral/efeitos dos fármacos , Pirazinas/farmacologia , Ribavirina/farmacologia , Hidroxilaminas/farmacologia , Linhagem Celular Tumoral , Linhagem CelularRESUMO
BACKGROUND: Respiratory syncytial virus (RSV) is a single-stranded RNA virus that commonly causes symptoms of upper respiratory tract infections in humans, with a clear seasonal trend. However, in immunocompromised and elderly patients, RSV infections still result in high rates of hospitalization and even risk of death. METHODS: We report a case of RSV infection in an adult with immunodeficiency, which initially showed only mild symptoms of upper respiratory tract infection, which did not improve after receiving empirical anti-infective treatment, and the foci of infection in the lungs continued to expand, which led to the aggravation of the disease. The diagnosis of RSV infection was finally confirmed by electron bronchoscopy and pathogenetic examination of the bronchoalveolar lavage fluid. The patient was given intravenous ribavirin treatment for one week. After one week of intravenous ribavirin treatment, the patient's symptoms improved significantly. A repeat chest CT suggested that the lung lesions were smaller than before. In order to improve clinicians' awareness of this disease, we jointly conducted a literature analysis. RESULTS: The final diagnosis of RSV was made by analyzing the patient's history, symptoms, and signs and performing relevant examinations. CONCLUSIONS: For patients with poor results of empirical application of antibiotics, electronic bronchoscopy and pathogenetic examination should be carried out at an early stage to clarify the nature of the lesions and to avoid rapid deterioration of the condition leading to life-threatening conditions in the patients. More consideration should be given to the possibility of disease diagnosis to avoid misdiagnosis and underdiagnosis, and appropriate treatment should be given at an early stage.
Assuntos
Antivirais , Infecções por Vírus Respiratório Sincicial , Ribavirina , Humanos , Infecções por Vírus Respiratório Sincicial/diagnóstico , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Antivirais/uso terapêutico , Antivirais/administração & dosagem , Ribavirina/uso terapêutico , Ribavirina/administração & dosagem , Masculino , Líquido da Lavagem Broncoalveolar/virologia , Hospedeiro Imunocomprometido , Broncoscopia , Adulto , Tomografia Computadorizada por Raios X , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
The association between chronic HCV infection and type 2 diabetes mellitus (T2DM) has been established; however, there is limited research on ß-cell function particularly in the pre-diabetic population. Here, we evaluated indices of ß-cell function and insulin sensitivity across the spectrum from normal glucose tolerance to T2DM in individuals with and without chronic hepatitis C (CHC), and the effects of antiviral treatments on these variables. A total of 153 non-cirrhotic, non-fibrotic CHC patients with a BMI <25 were enrolled in the study. Among them, 119 were successfully treated with either direct acting antiviral (DAA) drugs or pegylated interferon/ribavirin (IFN/RBV) anti-HCV therapy. Fasting state- and oral glucose tolerance test (OGTT)-derived indexes were used to evaluate ß-cell function and insulin sensitivity. Among all subjects, 19 (13%) had T2DM and 21% exhibited pre-diabetes including 8% isolated impaired fasting glucose (IFG) and 13% combined IFG and impaired glucose tolerance (IGT). Early and total insulin secretion adjusted for the degree of insulin resistance were decreased in pre-diabetic CHC patients compared to HCV-uninfected individuals. Viral eradication through DAA or IFN/RBV therapy demonstrated positive impacts on insulin sensitivity and ß-cell function in CHC patients who achieved sustained virologic response (SVR), regardless of fasting or OGTT state. These findings emphasize the role of HCV in the development of ß-cell dysfunction, while also suggesting that viral eradication can improve insulin secretion, reverse insulin resistance, and ameliorate glycemic control. These results have important implications for managing pre-diabetic CHC patients and could prevent diabetes-related clinical manifestations and complications.
Assuntos
Antivirais , Diabetes Mellitus Tipo 2 , Teste de Tolerância a Glucose , Hepatite C Crônica , Resistência à Insulina , Células Secretoras de Insulina , Ribavirina , Humanos , Masculino , Feminino , Antivirais/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/virologia , Pessoa de Meia-Idade , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Hepatite C Crônica/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Adulto , Ribavirina/uso terapêutico , Glicemia/análise , Resposta Viral Sustentada , Idoso , Insulina/uso terapêutico , Estado Pré-Diabético/tratamento farmacológico , Estado Pré-Diabético/virologiaRESUMO
BACKGROUND: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. METHODS: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events. RESULTS: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). CONCLUSION: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.
Assuntos
Antivirais , Carcinoma Hepatocelular , Hepatite C Crônica , Cirrose Hepática , Neoplasias Hepáticas , Resposta Viral Sustentada , Humanos , Taiwan/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/prevenção & controle , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/prevenção & controle , Carcinoma Hepatocelular/virologia , Cirrose Hepática/epidemiologia , Cirrose Hepática/virologia , Adulto , Idoso , Ribavirina/uso terapêutico , Estudos de Coortes , Sistema de Registros , Incidência , Quimioterapia Combinada , Modelos de Riscos Proporcionais , Resultado do TratamentoRESUMO
α-Synuclein (α-syn) is an intrinsically disordered protein, linked genetically and neuropathologically to Parkinson's disease where this protein aggregates within the brain. Hence, identifying compounds capable of impeding α-syn aggregation puts forward a promising approach for the development of disease-modifying therapies. Herein, we investigated the efficacy of Ribavirin, an FDA-approved compound, in curtailing α-syn amyloid transformation, employing an array of bioinformatic tools and systematic analysis using biophysical techniques. Ribavirin shows a dose dependent anti-aggregation propensity where it effectively subdued the formation of mature fibrillar aggregates of α-syn, where even at the lowest concentration there was a 69â¯% reduction in the ThT maxima. Ribavirin averts the formation of mature fibrillar aggregates by interacting with the NAC domain of α-syn. Ribavirin redirects the amyloid transformation of α-syn by emanating aggregates of lower order with reduced cross ß-sheet signature and revokes the formation of on-pathway amyloids. Collectively, our study puts forward the novel potency of Ribavirin as a promising molecule for therapeutic intervention in Parkinson's disease.
Assuntos
Amiloide , Antivirais , Ribavirina , alfa-Sinucleína , alfa-Sinucleína/metabolismo , alfa-Sinucleína/antagonistas & inibidores , alfa-Sinucleína/química , Antivirais/farmacologia , Antivirais/química , Ribavirina/farmacologia , Ribavirina/química , Humanos , Amiloide/metabolismo , Amiloide/química , Amiloide/antagonistas & inibidores , Amiloide/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Relação Dose-Resposta a DrogaRESUMO
Ribavirin (RBV), which is extensively used to treat viral diseases such as COVID-19, is considered one of the major emerging contaminants due to its long-term existence and health risk in the aqueous environmental system. However, research on effective removal of RBV still remains insufficient. In this study, we investigated the RBV degradation kinetics and mechanism in UV/chlorine/Fe(II) process. The degradation rate constant kobs-RBV of RBV was 2.52 × 10-4 s-1 in UV/chlorine/Fe(II) process, which increased by 1.6 times and 1.3 times than that in chlorine alone and UV/chlorine process, respectively. Notably, trace amount Fe(II) promoted RBV degradation in UV/chlorine system through Fe2+/Fe3+ cycles, enhancing the yield of reactive species such as HO· and certain species reactive chlorine radicals (RCS). The contributions of HO· and RCS toward RBV degradation were 53.91% and 16.11%, respectively. Specifically, Cl·, ClO·, and Cl2·- were responsible for 8.59%, 2.69%, and 4.83% of RBV removal. The RBV degradation pathway indicated that the reactive species preferentially attacked the amide moiety of RBV, which cleaved the ether bond and the hydroxyl group. The toxicity evaluation of RBV degradation products elucidated that UV/chlorine/Fe(II) process was beneficial for RBV detoxification.
Assuntos
Cloro , Ferro , Ribavirina , Raios Ultravioleta , Poluentes Químicos da Água , Purificação da Água , Purificação da Água/métodos , Cloro/química , Poluentes Químicos da Água/química , Ribavirina/química , Ferro/química , CinéticaRESUMO
BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a zoonotic infectious disease caused by the severe fever with thrombocytopenia syndrome virus (SFTSV). Endemic in East Asia, SFTS is characterized by an exceptionally high mortality rate. Presently, there is no established treatment for SFTS, particularly for patients in critical condition. In this study, we collected and analyzed laboratory and clinical data from 92 critically ill patients with SFTS treated at Weihai Municipal Hospital between 2019 and 2022. We hope that our study will provide some hints for the treatment of critically ill patients with SFTS. METHODS: A total of 92 critically ill patients with SFTS were included in this study. Of these patients, 45 received treatment with therapeutic plasma exchange (TPE) and ribavirin (referred to as the TPE group), while the remaining patients received only ribavirin (referred to as the non-TPE group). Clinical and laboratory parameters were analyzed retrospectively. RESULTS: The results showed significant improvements in multiple laboratory parameters following treatment with TPE and ribavirin, including white blood cell and neutrophil count, lactate dehydrogenase, creatine kinase isoenzyme-MB, prothrombin time, activated partial thromboplastin time, D-Dimer, serum sodium and copies of virus genomes. The combination of TPE with ribavirin demonstrated a significant reduction in mortality rates, with a mortality rate of 20.0% in the TPE group compared to 40.4% in the non-TPE group (P = 0.033). CONCLUSIONS: Our findings suggest that critically ill patients with SFTS who received TPE and ribavirin experienced improvements in both clinical and laboratory parameters. These results indicate that TPE combined with ribavirin may represent a promising novel therapeutic approach for managing critically ill patients with SFTS. However, comparative studies of large sample size or randomized clinical trials are warranted to confirm the effectiveness of this combination therapy in the treatment of severe SFTS cases.
Assuntos
Estado Terminal , Troca Plasmática , Ribavirina , Febre Grave com Síndrome de Trombocitopenia , Humanos , Ribavirina/uso terapêutico , Troca Plasmática/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Febre Grave com Síndrome de Trombocitopenia/terapia , Febre Grave com Síndrome de Trombocitopenia/tratamento farmacológico , Antivirais/uso terapêutico , Adulto , Terapia CombinadaRESUMO
Hepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans. Recent data suggest that HEV has a very heterogeneous hypervariable region (HVR), which can tolerate major genomic rearrangements. In this study, we identify insertions of previously undescribed sequence snippets in serum samples of a ribavirin treatment failure patient. These insertions increase viral replication while not affecting sensitivity towards ribavirin in a subgenomic replicon assay. All insertions contain a predicted nuclear localization sequence and alanine scanning mutagenesis of lysine residues in the HVR influences viral replication. Sequential replacement of lysine residues additionally alters intracellular localization in a fluorescence dye-coupled construct. Furthermore, distinct sequence patterns outside the HVR are identified as viral determinants that recapitulate the enhancing effect. In conclusion, patient-derived insertions can increase HEV replication and synergistically acting viral determinants in and outside the HVR are described. These results will help to understand the underlying principles of viral adaptation by viral- and host-sequence snatching during the clinical course of infection.
Assuntos
Vírus da Hepatite E , Hepatite E , Ribavirina , Replicação Viral , Replicação Viral/genética , Vírus da Hepatite E/genética , Vírus da Hepatite E/fisiologia , Vírus da Hepatite E/efeitos dos fármacos , Humanos , Hepatite E/virologia , Hepatite E/tratamento farmacológico , Ribavirina/farmacologia , Mutagênese Insercional , Antivirais/farmacologia , RNA Viral/genética , Genoma Viral , Replicon/genéticaRESUMO
BACKGROUND: 10 million people are chronically infected with the hepatitis C virus (HCV) in sub-Saharan Africa. The assessment of viral genotypes and treatment response in this region is necessary to achieve the WHO target of worldwide elimination of viral hepatitis by 2030. We aimed to investigate the prevalence of HCV genotypes and outcomes of treatment with direct-acting antiviral agents in Benin, a country with a national HCV seroprevalence of 4%. METHODS: This prospective cohort study was conducted at two referral hospitals in Benin. Individuals were eligible for inclusion if they were seropositive for HCV and willing to consent to participation in the study; exclusion criteria were an inability to give consent or incarceration. Viraemia was confirmed by PCR. The primary outcomes were to identify HCV genotypes and measure sustained virological response rates 12 weeks after completion of treatment (SVR12) with a 12-week course of sofosbuvir-velpatasvir or sofosbuvir-ledipasvir, with or without ribavirin. We conducted phylogenetic and resistance analyses after the next-generation sequencing of samples with a cycle threshold (Ct) value of 30 or fewer cycles. The in-vitro efficacy of NS5A inhibitors was tested using a subgenomic replicon assay. FINDINGS: Between June 2, 2019, and Dec 30, 2020, 148 individuals were screened for eligibility, of whom 100 were recruited prospectively to the study. Plasma samples from 79 (79%) of the 100 participants were positive for HCV by PCR. At the time of the study, 52 (66%) of 79 patients had completed treatment, with an SVR12 rate of 94% (49 of 52). 57 (72%) of 79 samples had a Ct value of 30 or fewer cycles and were suitable for whole-genome sequencing, from which we characterised 29 (51%) samples as genotype 1 and 28 (49%) as genotype 2. Three new genotype 1 subtypes (1q, 1r, and 1s) and one new genotype 2 subtype (2xa) were identified. The most commonly detected subtype was 2d (12 [21%] of 57 samples), followed by 1s (eight [14%]), 1r (five [9%]), 1b (four [7%]), 1q (three [5%]), 2xa (three [5%]), and 2b (two [3%]). 20 samples (11 genotype 2 and nine genotype 1) were unassigned new singleton lineages. 53 (93%) of 57 sequenced samples had at least two resistance-associated substitutions within the NS5A gene. Subtype 2d was associated with a lower-than-expected SVR12 rate (eight [80%] of ten patients). For one patient, with subtype 2b, treatment was not successful. INTERPRETATION: This study revealed a high SVR rate in Benin among individuals treated for HCV with sofosbuvir-velpatasvir, including those with highly diverse viral genotypes. Further studies of treatment effectiveness in genotypes 2d and 2b are indicated. FUNDING: Medical Research Council, Wellcome, Global Challenges Research Fund, Academy of Medical Sciences, and PHARMBIOTRAC.
Assuntos
Antivirais , Genótipo , Hepacivirus , Filogenia , Sofosbuvir , Humanos , Hepacivirus/genética , Hepacivirus/efeitos dos fármacos , Benin/epidemiologia , Estudos Prospectivos , Antivirais/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Sofosbuvir/uso terapêutico , Resultado do Tratamento , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Hepatite C Crônica/epidemiologia , Resposta Viral Sustentada , Ribavirina/uso terapêutico , Farmacorresistência Viral/genética , Carbamatos/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Fluorenos/uso terapêutico , Prevalência , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepatite C/virologia , Benzimidazóis , Combinação de MedicamentosRESUMO
Lung cancer is among leading causes of death worldwide. The five-year survival rate of this disease is extremely low (17.8 %), mainly due to difficult early diagnosis and to the limited efficacy of currently available chemotherapeutics. This underlines the necessity to develop innovative therapies for lung cancer. In this context, drug repurposing represents a viable approach, as it reduces the turnaround time of drug development removing costs associated to safety testing of new molecular entities. Ribavirin, an antiviral molecule used to treat hepatitis C virus infections, is particularly promising as repurposed drug for cancer treatment, having shown therapeutic activity against glioblastoma, acute myeloid leukemia, and nasopharyngeal carcinoma. In the present study, we thoroughly investigated the in vitro anticancer activity of ribavirin against A549 human lung adenocarcinoma cells. From a functional standpoint, ribavirin significantly inhibits cancer hallmarks such as cell proliferation, migration, and colony formation. Mechanistically, ribavirin downregulates the expression of numerous proteins and genes regulating cell migration, proliferation, apoptosis, and cancer angiogenesis. The anticancer potential of ribavirin was further investigated in silico through gene ontology pathway enrichment and protein-protein interaction networks, identifying five putative molecular interactors of ribavirin (Erb-B2 Receptor Tyrosine Kinase 4 (Erb-B4); KRAS; Intercellular Adhesion Molecule 1 (ICAM-1); amphiregulin (AREG); and neuregulin-1 (NRG1)). These interactions were characterized via molecular docking and molecular dynamic simulations. The results of this study highlight the potential of ribavirin as a repurposed chemotherapy against lung cancer, warranting further studies to ascertain the in vivo anticancer activity of this molecule.
Assuntos
Antineoplásicos , Proliferação de Células , Reposicionamento de Medicamentos , Neoplasias Pulmonares , Ribavirina , Humanos , Reposicionamento de Medicamentos/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Ribavirina/farmacologia , Células A549 , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Movimento Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Simulação de Acoplamento Molecular , Antivirais/farmacologia , Biologia Computacional/métodos , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismoAssuntos
Vírus da Hepatite E , Hepatite E , Quinase I-kappa B , Hepatite E/diagnóstico , Hepatite E/genética , Hepatite E/imunologia , Hepatite E/terapia , Feminino , Pessoa de Meia-Idade , Quinase I-kappa B/genética , Mutação , Ribavirina/uso terapêutico , Vírus da Hepatite E/fisiologia , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Evolução Fatal , Hepatite Crônica/diagnóstico , Hepatite Crônica/genética , Hepatite Crônica/imunologia , Hepatite Crônica/terapia , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologiaRESUMO
INTRODUCTION: Zika virus (ZIKV) is a flavivirus transmitted through the bites of infected Aedes mosquitoes. These viruses can also be transmitted through sexual contact, vertical transmission, and possibly transfusion. Most cases are asymptomatic, but symptoms can include rash, conjunctivitis, fever, and arthralgia, which are characteristic of other arboviruses. Zika infection can lead to complications such as microcephaly, miscarriage, brain abnormalities, and Guillain-Barré syndrome (GBS). OBJECTIVE: The aim is to determine the inhibitory potential of the algae Kappaphycus alvarezii (K. alvarezii) on ZIKV replication. METHODOLOGY: Cytotoxicity experiments were performed using Vero cells to determine the CC50, and ZIKV replication inhibition assays (ATCC® VR-1839™) were conducted to determine the EC50. The mechanism of action was also studied to assess any synergistic effect with Ribavirin. RESULTS: K. alvarezii demonstrated low toxicity with a CC50 of 423 µg/mL and a potent effect on ZIKV replication with an EC50 of 0.65 µg/mL and a Selectivity Index (SI) of 651, indicating the extract's safety. Virucidal effect assays were carried out to evaluate the possible mechanism of action, and the compound addition time was studied, showing the potential to delay the treatment of infected cells by up to 6 hours. A potential synergistic effect was observed when K. alvarezii extract was combined with suboptimal concentrations of Ribavirin, resulting in 99% inhibition of viral replication. CONCLUSION: Our data demonstrate the significant potential of K. alvarezii extract and highlight the need for further studies to investigate its mechanism of action. We propose this extract as a potential anti-Zika compound.
Assuntos
Antivirais , Alga Marinha , Replicação Viral , Zika virus , Antivirais/farmacologia , Antivirais/química , Zika virus/efeitos dos fármacos , Animais , Chlorocebus aethiops , Células Vero , Alga Marinha/química , Replicação Viral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Ribavirina/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Algas Comestíveis , RodófitasRESUMO
The treatment of HCV and its sequelae are used to be predominantly based on Interferon (IFN). However, this was associated with significant adverse events as a result of its immunostimulant capabilities. Since their introduction, the directly acting antiviral drugs (DAAs), have become the standard of care to treat of HCV and its complications including mixed cryoglobulinemic vasculitis (MCV). In spite of achieving sustained viral response (SVR), there appeared many reports describing unwelcome complications such as hepatocellular and hematological malignancies as well as relapses. Prolonged inflammation induced by a multitude of factors, can lead to DNA damage and affects BAFF and APRIL, which serve as markers of B-cell proliferation. We compared, head-to-head, three antiviral protocols for HCV-MCV treatment As regards the treatment response and relapse, levels of BAFF and APRIL among pegylated interferon α-based and free regimens (Sofosbuvir + Ribavirin; SOF-RIBA, Sofosbuvir + Daclatasvir; SOF-DACLA). Regarding clinical response HCV-MCV and SVR; no significant differences could be identified among the 3 different treatment protocols, and this was also independent form using IFN. We found no significant differences between IFN-based and free regimens DNA damage, markers of DNA repair, or levels of BAFF and APRIL. However, individualized drug-to-drug comparisons showed many differences. Those who were treated with IFN-based protocol showed decreased levels of DNA damage, while the other two IFN-free groups showed increased DNA damage, being the worst in SOF-DACLA group. There were increased levels of BAFF through follow-up periods in the 3 protocols being the best in SOF-DACLA group (decreased at 24 weeks). In SOF-RIBA, CGs relapsed significantly during the follow-up period. None of our patients who were treated with IFN-based protocol had significant clinico-laboratory relapse. Those who received IFN-free DAAs showed a statistically significant relapse of constitutional manifestations. Our findings suggest that IFN-based protocols are effective in treating HCV-MCV similar to IFN-free protocols. They showed lower levels of DNA damage and repair. We believe that our findings may offer an explanation for the process of lymphoproliferation, occurrence of malignancies, and relapses by shedding light on such possible mechanisms.
Assuntos
Antivirais , Crioglobulinemia , Vasculite , Humanos , Crioglobulinemia/tratamento farmacológico , Crioglobulinemia/etiologia , Antivirais/uso terapêutico , Masculino , Vasculite/tratamento farmacológico , Vasculite/virologia , Pessoa de Meia-Idade , Feminino , Idoso , Hepacivirus/efeitos dos fármacos , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Imidazóis/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico , Pirrolidinas/uso terapêutico , Fator Ativador de Células B , Interferon-alfa/uso terapêutico , Quimioterapia Combinada , Hepatite C/tratamento farmacológico , Hepatite C/complicações , Hepatite C/virologia , Resultado do Tratamento , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , CarbamatosRESUMO
Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.
Assuntos
Antivirais , Hepacivirus , Sofosbuvir , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , África Central , África Ocidental , Ácidos Aminoisobutíricos , Antivirais/uso terapêutico , Antivirais/efeitos adversos , Benzimidazóis/uso terapêutico , Benzimidazóis/efeitos adversos , Benzopiranos , Carbamatos/uso terapêutico , Ciclopropanos/uso terapêutico , Ciclopropanos/efeitos adversos , Quimioterapia Combinada , Estudos de Viabilidade , Fluorenos/uso terapêutico , Fluorenos/efeitos adversos , Genótipo , Hepacivirus/genética , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Prolina/análogos & derivados , Prolina/uso terapêutico , Quinoxalinas , Ribavirina/uso terapêutico , Ribavirina/efeitos adversos , Sofosbuvir/uso terapêutico , Sofosbuvir/efeitos adversos , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Resposta Viral Sustentada , Resultado do TratamentoRESUMO
Hepatitis E virus is a single-strand, positive-sense RNA virus that can lead to chronic infection in immunocompromised patients. Virus-host recombinant variants (VHRVs) have been described in such patients. These variants integrate part of human genes into the polyproline-rich region that could introduce new post-translational modifications (PTMs), such as ubiquitination. The aim of this study was to characterize the replication capacity of different VHRVs, namely, RNF19A, ZNF787, KIF1B, EEF1A1, RNA18, RPS17, and RPL6. We used a plasmid encoding the Kernow strain, in which the fragment encoding the S17 insertion was deleted (Kernow p6 delS17) or replaced by fragments encoding the different insertions. The HEV RNA concentrations in the supernatants and the HepG2/C3A cell lysates were determined via RT-qPCR. The capsid protein ORF2 was immunostained. The effect of ribavirin was also assessed. The HEV RNA concentrations in the supernatants and the cell lysates were higher for the variants harboring the RNF19A, ZNF787, KIF1B, RPS17, and EEF1A1 insertions than for the Kernow p6 del S17, while it was not with RNA18 or RPL6 fragments. The number of ORF2 foci was higher for RNF19A, ZNF787, KIF1B, and RPS17 than for Kernow p6 del S17. VHRVs with replicative advantages were less sensitive to the antiviral effect of ribavirin. No difference in PTMs was found between VHRVs with a replicative advantage and those without. In conclusion, our study showed that insertions did not systematically confer a replicative advantage in vitro. Further studies are needed to determine the mechanisms underlying the differences in replicative capacity. IMPORTANCE: Hepatitis E virus (HEV) is a major cause of viral hepatitis. HEV can lead to chronic infection in immunocompromised patients. Ribavirin treatment is currently used to treat such chronic infections. Recently, seven virus-host recombinant viruses were characterized in immunocompromised patients. These viruses have incorporated a portion of a human gene fragment into their genome. We studied the consequences of these insertions on the replication capacity. We found that these inserted fragments could enhance virus replication for five of the seven recombinant variants. We also showed that the recombinant variants with replicative advantages were less sensitive to ribavirin in vitro. Finally, we found that the mechanisms leading to such a replicative advantage do not seem to rely on the post-translational modifications introduced by the human gene fragment that could have modified the function of the viral protein. The mechanisms involved in improving the replication of such recombinant viruses remain to be explored.
Assuntos
Vírus da Hepatite E , Interações entre Hospedeiro e Microrganismos , Recombinação Genética , Humanos , Antivirais/farmacologia , Células Hep G2 , Hepatite E/genética , Hepatite E/virologia , Vírus da Hepatite E/classificação , Vírus da Hepatite E/efeitos dos fármacos , Vírus da Hepatite E/genética , Vírus da Hepatite E/crescimento & desenvolvimento , Processamento de Proteína Pós-Traducional , Ribavirina/farmacologia , RNA Viral/genética , RNA Viral/metabolismo , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética , Interações entre Hospedeiro e Microrganismos/genética , Ubiquitinação/genética , Plasmídeos/genéticaRESUMO
Lassa virus (LASV), a risk-group 4 pathogen, must be handled in biosafety level-4 (BSL-4) conditions, thereby limiting its research and antiviral development. Here, we developed a novel LASV reverse genetics system which, to our knowledge, is the first to study the complete LASV life cycle under BSL-2 conditions. Viral particles can be produced efficiently when LASV minigenomic RNA harbouring minimal viral cis-elements and reporter genes is transfected into a helper cell line stably expressing viral NP, GP, Z and L proteins. The resulting defective virions, named LASVmg, can propagate only in the helper cell line, providing a BSL-2 model to study the complete LASV life cycle. Using this model, we found that a previously reported cellular receptor α-dystroglycan is dispensable for LASVmg infection. Furthermore, we showed that ribavirin can inhibit LASVmg infection by inducing viral mutations. This new BSL-2 system should facilitate studying the LASV life cycle and screening antivirals.
Assuntos
Vírus Lassa , Genética Reversa , Vírus Lassa/genética , Vírus Lassa/fisiologia , Genética Reversa/métodos , Humanos , Animais , Antivirais/farmacologia , Chlorocebus aethiops , Linhagem Celular , Replicação Viral , Febre Lassa/virologia , Ribavirina/farmacologia , Células Vero , Contenção de Riscos Biológicos , Genoma Viral , Vírion/genética , Vírion/metabolismoRESUMO
Respiratory syncytial virus (RSV) is a major public health problem that has undergone significant changes in recent years. First of all, it has become easier to diagnose with highly reliable and rapidly available confirmatory tests. This has led to a better understanding of its epidemiology and RSV has gone from being a disease of the pediatric age group, severe only in infants and immunosuppressed children, to being a common disease in people of all ages, particularly important in patients of advanced age or with immunosuppressive diseases. Recent therapeutic and prophylactic advances, both with long-lasting monoclonal antibodies and vaccines, are another reason for satisfaction. For these reasons, the COVID and Emerging Pathogens Committee of the Illustrious Official College of Physicians of Madrid (ICOMEM) has considered it pertinent to review this subject in the light of new knowledge and new resources for dealing with this infection. We have formulated a series of questions that we believe will be of interest not only to members of the College but also to any non-expert in this subject, with a particular focus on the situation of RSV infection in Spain. (AU)
El Virus Respiratorio Sincitial (VRS), es un problema de salud pública de primera magnitud que en años recientes ha experimentado cambios muy importantes. En primer lugar, se ha producido una mayor facilidad diagnóstica con pruebas confirmatorias altamente fiables y rápidamente disponibles. Esto ha permitido conocer mejor su epidemiología y VRS ha pasado de ser una enfermedad de la edad pediátrica, grave sólo en lactantes y niños inmunodeprimidos, a ser una enfermedad común en personas de toda edad, particularmente importante en pacientes de edades avanzadas o con enfermedades que inmunodeprimen. Los avances terapéuticos y profilácticos, recientes, tanto con anticuerpos monoclonales de larga duración como con vacunas, constituyen otro motivo de satisfacción. Por estos motivos, el Comité de COVID y de patógenos emergentes del Ilustre Colegio Oficial de Médicos de Madrid (ICOMEM) ha considerado pertinente revisar este tema, a la luz de los nuevos conocimientos y de los nuevos recursos para afrontar esta infección. Hemos formulado una serie de preguntas que creemos de interés no sólo para los colegiados si no para cualquier persona no experta en este tema, con una vista particular en la situación de la infección por VRS en España. (AU)