The host-targeting compound peruvoside has a broad-spectrum antiviral activity against positive-sense RNA viruses

Positive-sense RNA viruses modify intracellular calcium stores, endoplasmic reticulum and Golgi apparatus (Golgi) to generate membranous replication organelles known as viral factories. Viral factories provide a conducive and substantial enclave for essential virus replication via concentrating necessary cellular factors and viral proteins in proximity. Here, we identified the vital role of a broad-spectrum antiviral, peruvoside in limiting the formation of viral factories. Mechanistically, we revealed the pleiotropic cellular effect of Src and PLC kinase signaling via cyclin-dependent kinase 1 signaling leads to Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1) phosphorylation and Golgi vesiculation by peruvoside treatment. The ramification of GBF1 phosphorylation fosters GBF1 deprivation consequentially activating downstream antiviral signaling by dampening viral factories formation. Further investigation showed signaling of ERK1/2 pathway via cyclin-dependent kinase 1 activation leading to GBF1 phosphorylation at Threonine 1337 (T1337). We also showed 100% of protection in peruvoside-treated mouse model with a significant reduction in viral titre and without measurable cytotoxicity in serum. These findings highlight the importance of dissecting the broad-spectrum antiviral therapeutics mechanism and pave the way for consideration of peruvoside, host-directed antivirals for positive-sense RNA virus-mediated disease, in the interim where no vaccine is available.

In silico structure analysis of alphaviral RNA genomes shows diversity in the evasion of IFIT1-mediated innate immunity

The IFIT (interferon-induced proteins with tetratricopeptide repeats) family constitutes a major arm of the antiviral functionof type I interferon (IFN). Human IFIT1, the earliest discovered member of this family, inhibits several viruses of positivestrand RNA genome. IFIT1 specifically recognizes single-stranded RNA with canonical 7-methylguanylate cap at the 50 end(Cap0), and inhibits their translation by competing with eIF4E (eukaryotic initiation factor 4E), an essential factor for 50Caprecognition. Recently, a novel viral mechanism of IFIT1 suppression was reported, in which an RNA hairpin in the 50untranslated region (50UTR) of the viral genome prevented recognition by IFIT1 and enhanced virus growth. Here, I haveanalyzed the in silico predicted structures in the 50UTR of the genomes of the Alphaviruses, a large group of envelopedRNA virus with positive-sense single-stranded genome. The results uncovered a large ensemble of RNA secondarystructures of diverse size and shape in the different viruses, which showed little correspondence to the phylogeny of theviruses. Unexpectedly, the 50UTR of several viral genomes in this family did not fold into any structure, suggesting eithertheir extreme sensitivity to IFIT1 or the existence of alternative viral mechanisms of subverting IFIT1 function.