RESUMEN
Mayaro fever, caused by Mayaro virus (MAYV) is a sub-lethal disease with symptoms that are easily confused with those of dengue fever, except for polyarthralgia, which may culminate in physical incapacitation. Recently, outbreaks of MAYV have been documented in metropolitan areas, and to date, there is no therapy or vaccine available. Moreover, there is no information regarding the three-dimensional structure of the viral proteins of MAYV, which is important in the search for antivirals. In this work, we constructed a three-dimensional model of protein C of MAYV by homology modelling, and this was employed in a manner similar to that of receptors in virtual screening studies to evaluate 590 molecules as prospective antiviral agents. In vitro bioassays were utilized to confirm the potential antiviral activity of the flavonoid epicatechin isolated from Salacia crassifolia (Celastraceae). The virtual screening showed that six flavonoids were promising ligands for protein C. The bioassays showed potent antiviral action of epicatechin, which protected the cells from almost all of the effects of viral infection. An effective concentration (EC50) of 0.247 µmol/mL was observed with a selectivity index (SI) of 7. The cytotoxicity assay showed that epicatechin has low toxicity, with a 50% cytotoxic concentration (CC50) greater than 1.723 µmol/mL. Epicatechin was found to be twice as potent as the reference antiviral ribavirin. Furthermore, a replication kinetics assay showed a strong inhibitory effect of epicatechin on MAYV growth, with a reduction of at least four logs in virus production. Our results indicate that epicatechin is a promising candidate for further testing as an antiviral agent against Mayaro virus and other alphaviruses.
Asunto(s)
Alphavirus/química , Antígenos Virales/química , Antivirales/farmacología , Catequina/farmacología , Salacia/química , Proteínas Virales/química , Alphavirus/metabolismo , Animales , Antígenos Virales/metabolismo , Antivirales/química , Antivirales/aislamiento & purificación , Sitios de Unión , Catequina/química , Catequina/aislamiento & purificación , Chlorocebus aethiops , Ensayos Analíticos de Alto Rendimiento , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Ribavirina/química , Ribavirina/farmacología , Homología Estructural de Proteína , Interfaz Usuario-Computador , Células Vero , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Malaria is one of the most dangerous diseases in developing countries. The chemotherapy of malaria has been based on drugs developed more than half a century ago. These drugs are continuously losing their efficacy, mainly due to multi-drug resistance developed by the malaria-causing parasite. In the last three decades, artemisinin and artemisinin-like compounds have proven to be efficient alternatives to the chemotherapeutic control of malaria. These facts have led to an increasing interest in the development of Quantitative Structure Activity Relantioship (QSAR) models for these compounds. This work presents a critical view on some QSAR models, and shows that, due to lack of a rigorous selection of the descriptors entering the models, most of them are unable to accurately indicate the molecular cause of biological activity. Some reasons for the weakness of the published models are discussed.