RESUMEN
Recent outbreaks of dangerous viral infections, such as Ebola virus disease, Zika fever, etc., are forcing the search for new antiviral compounds. Preferably, such compounds should possess broad-spectrum antiviral activity, as the development of drugs for the treatment of dozens of viral infections lacking specific treatment would require significant resources. Antiviral activity data present in public resources are very sparse and further investigation of structure-activity relationships is necessary. One of the strategies could be the investigation of chemical space around known active compounds and assessment of activity against closely related viruses in order to fill in the antiviral activity matrix. Here we present an investigation of antiviral activity using universal maps built with generative topographic mapping (GTM) algorithm. The GTM-based maps were used to find commercially available compounds in close proximity to already known compounds with anti-flaviviral and anti-enteroviral activities. Selected compounds were then assessed in cell-based assays against tick-borne encephalitis virus (TBEV) and a panel of enteroviruses. This approach allowed us to identify 23 new compounds showing anti-TBEV activity with EC50 values in micromolar and submicromolar range.
Asunto(s)
Algoritmos , Antivirales/farmacología , Virus de la Encefalitis Transmitidos por Garrapatas/efectos de los fármacos , Animales , Antivirales/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , PorcinosRESUMEN
The phenoxazine scaffold is widely used to stabilize nucleic acid duplexes, as a part of fluorescent probes for the study of nucleic acid structure, recognition, and metabolism, etc. Here we present the synthesis of phenoxazine-based nucleoside derivatives and their antiviral activity against a panel of structurally diverse viruses: enveloped DNA herpesviruses varicella zoster virus (VZV) and human cytomegalovirus, enveloped RNA tick-borne encephalitis virus (TBEV), and non-enveloped RNA enteroviruses. Studied compounds were effective against DNA and RNA viruses reproduction in cell culture. 3-(2'-Deoxy-ß-D-ribofuranosyl)-1,3-diaza-2-oxophenoxazine proved to be a potent inhibitor of VZV replication with superior activity against wild type than thymidine kinase deficient strains (EC50 0.06 and 10⯵M, respectively). This compound did not show cytotoxicity on all the studied cell lines. Several compounds showed promising activity against TBEV (EC50 0.35-0.91⯵M), but the activity was accompanied by pronounced cytotoxicity. These compounds may be considered as a good starting point for further structure optimization as antiherpesviral or antiflaviviral compounds.