RESUMEN
The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti-virals. We combine in vitro RNA analysis with molecular dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5' UTR of the SARS-CoV-2 genome. Furthermore, we determine the binding of metallo-supramolecular helicates (cylinders) to this RNA structure. These nano-size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3-base bulge and the central cross 4-way junction located in stem loop 5. Finally, we show these RNA-binding cylinders suppress SARS-CoV-2 replication, highlighting their potential as novel anti-viral agents.
Asunto(s)
Regiones no Traducidas 5' , Antivirales/farmacología , Sustancias Macromoleculares/farmacología , ARN/metabolismo , SARS-CoV-2/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Animales , Antivirales/química , Antivirales/metabolismo , Chlorocebus aethiops , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacología , Genoma Viral/efectos de los fármacos , Sustancias Macromoleculares/química , Sustancias Macromoleculares/metabolismo , Metales Pesados/química , Simulación de Dinámica Molecular , ARN/genética , SARS-CoV-2/química , Células VeroRESUMEN
The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti-virals. We combine in vitro RNA analysis with molecular dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5' UTR of the SARS-CoV-2 genome. Furthermore, we determine the binding of metallo-supramolecular helicates (cylinders) to this RNA structure. These nano-size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3-base bulge and the central cross 4-way junction located in stem loop 5. Finally, we show these RNA-binding cylinders suppress SARS-CoV-2 replication, highlighting their potential as novel anti-viral agents.