RESUMEN
In the year 2015, new Zika virus (ZIKV) broke out in Brazil and spread away in more than 80 countries. Scientists directed their efforts toward viral polymerase in attempt to find inhibitors that might interfere with its function. In this study, molecular dynamics simulation (MDS) was performed over 444 ns for a ZIKV polymerase model. Molecular docking (MD) was then performed every 10 ns during the MDS course to ensure the binding of small molecules to the polymerase over the entire time of the simulation. MD revealed the binding ability of four suggested guanosine inhibitors (GIs); (Guanosine substituted with OH and SH (phenyl) oxidanyl in the 2' carbon of the ribose ring). The GIs were compared to guanosine triphosphate (GTP) and five anti-hepatitis C virus drugs (either approved or under clinical trials). The mode of binding and the binding performance of GIs to ZIKV polymerase were found to be the same as GTP. Hence, these compounds were capable of competing GTP for the active site. Moreover, GIs bound to ZIKV active site more tightly compared to ribavirin, the wide-range antiviral drug.
Asunto(s)
Antivirales/metabolismo , Antivirales/farmacología , Nucleótidos/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/metabolismo , Virus Zika/efectos de los fármacos , Virus Zika/metabolismo , Antivirales/química , Sitios de Unión , Brasil , Guanosina/antagonistas & inhibidores , Guanosina Trifosfato/análogos & derivados , Guanosina Trifosfato/química , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Virus Zika/enzimologíaRESUMEN
In 2015, European and U.S. health agencies issued warning letters in response to 9 reported clinical cases of severe bradycardia/bradyarrhythmia in hepatitis C virus (HCV)-infected patients treated with sofosbuvir (SOF) in combination with other direct acting antivirals (DAAs) and the antiarrhythmic drug, amiodarone (AMIO). We utilized preclinical in vivo models to better understand this cardiac effect, the potential pharmacological mechanism(s), and to identify a clinically translatable model to assess the drug-drug interaction (DDI) cardiac risk of current and future HCV inhibitors. An anesthetized guinea pig model was used to elicit a SOF+AMIO-dependent bradycardia. Detailed cardiac electrophysiological studies in this species revealed SOF+AMIO-dependent selective nodal dysfunction, with initial, larger effects on the sinoatrial node. Further studies in conscious, rhesus monkeys revealed an emergent bradycardia and bradyarrhythmia in 3 of 4 monkeys administered SOF+AMIO, effects not observed with either agent alone. Morever, bradycardia and bradyarrhythmia were not observed in rhesus monkeys when intravenous infusion of MK-3682 was completed after AMIO pretreatment. CONCLUSIONS: These are the first preclinical in vivo experiments reported to replicate the severe clinical SOF+AMIO cardiac DDI and provide potential in vivo mechanism of action. As such, these data provide a preclinical risk assessment paradigm, including a clinically relevant nonhuman primate model, with which to better understand cardiovascular DDI risk for this therapeutic class. Furthermore, these studies suggest that not all HCV DAAs and, in particular, not all HCV nonstructural protein 5B inhibitors may exhibit this cardiac DDI with amiodarone. Given the selective in vivo cardiac electrophysiological effect, these data enable targeted cellular/molecular mechanistic studies to more precisely identify cell types, receptors, and/or ion channels responsible for the clinical DDI. (Hepatology 2016;64:1430-1441).
Asunto(s)
Amiodarona/farmacología , Antiarrítmicos/farmacología , Antivirales/farmacología , Corazón/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Nucleótidos/antagonistas & inhibidores , Sofosbuvir/farmacología , Amiodarona/efectos adversos , Animales , Antiarrítmicos/efectos adversos , Antivirales/efectos adversos , Interacciones Farmacológicas , Cobayas , Corazón/fisiología , Macaca mulatta , Masculino , Sofosbuvir/efectos adversosRESUMEN
Thymidine kinase is a key enzyme responsible for the activation of several anticancer and antiviral drugs. As the first enzyme in the salvage pathway of thymidine, it is regulated by the feedback inhibition exerted by the end-product of the pathway, namely thymidine 5'-triphosphate. 5'-Aminothymidine is a non-toxic analogue of thymidine capable of interfering with this regulatory mechanism. In fact, it has been shown that 5'-aminothymidine increases the cytotoxicity and metabolism of various thymidine analogues currently in use of the clinic as antineoplastic agents. This mini-review article focuses in the evidence supporting the role of 5'-aminothymidine as a potential prototype drug for a new class of anticancer agents: drugs which affect the regulation of key metabolic pathways that determine the efficacy of agents with cytotoxic activity. The mechanism of action, antineoplastic activities and basis for selectivity in tissue culture models are also described.
Asunto(s)
Antineoplásicos/farmacología , Timidina Quinasa/metabolismo , Timidina/análogos & derivados , Animales , Antineoplásicos/farmacocinética , Antivirales/farmacocinética , Biotransformación/efectos de los fármacos , Chlorocebus aethiops , Daño del ADN/efectos de la radiación , Diseño de Fármacos , Retroalimentación/efectos de los fármacos , Floxuridina/farmacocinética , Células HeLa/efectos de los fármacos , Células HeLa/enzimología , Humanos , Idoxuridina/farmacocinética , Idoxuridina/toxicidad , Proteínas de Neoplasias/metabolismo , Nucleótidos/antagonistas & inhibidores , Fármacos Sensibilizantes a Radiaciones/farmacología , Timidina/farmacología , Células Tumorales Cultivadas , Vejiga Urinaria/enzimología , Neoplasias de la Vejiga Urinaria/enzimología , Neoplasias de la Vejiga Urinaria/patología , Células Vero/efectos de los fármacos , Células Vero/enzimologíaRESUMEN
Thymidine kinase is a key enzyme responsible for the activation of several anticancer and antiviral drugs. As the first enzyme in the salvage pathway of thymidine, it is regulated by the feedback inhibition exerted by the end-product of the pathway, namely thymidine 5'-triphosphate. 5'-Aminothymidine is a non-toxic analogue of thymidine capable of interfering with this regulatory mechanism. In fact, it has been shown that 5'-aminothymidine increases the cytotoxicity and metabolism of various thymidine analogues currently in use of the clinic as antineoplastic agents. This mini-review article focuses in the evidence supporting the role of 5'-aminothymidine as a potential prototype drug for a new class of anticancer agents: drugs which affect the regulation of key metabolic pathways that determine the efficacy of agents with cytotoxic activity. The mechanism of action, antineoplastic activities and basis for selectivity in tissue culture models are also described