RESUMEN
Alphaviruses are a large group of re-emerging arthropod-borne RNA viruses. The compact viral RNA genomes harbor diverse structures that facilitate replication. These structures can be recognized by antiviral cellular RNA-binding proteins, including DExD-box (DDX) helicases, that bind viral RNAs to control infection. The full spectrum of antiviral DDXs and the structures that are recognized remain unclear. Genetic screening identified DDX39A as antiviral against the alphavirus chikungunya virus (CHIKV) and other medically relevant alphaviruses. Upon infection, the predominantly nuclear DDX39A accumulates in the cytoplasm inhibiting alphavirus replication, independent of the canonical interferon pathway. Biochemically, DDX39A binds to CHIKV genomic RNA, interacting with the 5' conserved sequence element (5'CSE), which is essential for the antiviral activity of DDX39A. Altogether, DDX39A relocalization and binding to a conserved structural element in the alphavirus genomic RNA attenuates infection, revealing a previously unknown layer to the cellular control of infection.
Asunto(s)
Fiebre Chikungunya , Virus Chikungunya , Humanos , Virus Chikungunya/genética , Línea Celular , Fiebre Chikungunya/metabolismo , ARN Helicasas/metabolismo , Replicación Viral/genética , ARN Viral/genética , ARN Viral/metabolismo , Antivirales/farmacología , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismoRESUMEN
Electron-rich, electron-deficient, and non-activated alkenes can be rapidly functionalized by in situ-generated difluoromethyl nitrile oxide. The (3+2) cycloaddition proceeds at room temperature, has broad functional group tolerance, and can be used for the late-stage modification of bioactive molecules (finasteride and carbamazepine). The obtained CF2H-isoxazolines can be easily transformed into CF2H-containing building blocks for medicinal chemistry: amines, amino acids, amino alcohols, and spirocyclic scaffolds.