Abstract
Therapeutic targeting of host cell factors required for virus replication rather than of pathogen components opens new perspectives to counteract virus infections. Anticipated advantages of this approach include a heightened barrier against the development of viral resistance and a broadened pathogen target spectrum. Myxoviruses are predominantly associated with acute disease and thus are particularly attractive for this approach since treatment time can be kept limited. To identify inhibitor candidates, we have analyzed hit compounds that emerged from a large-scale high-throughput screen for their ability to block replication of members of both the orthomyxovirus and paramyxovirus families. This has returned a compound class with broad anti-viral activity including potent inhibition of different influenza virus and paramyxovirus strains. After hit-to-lead chemistry, inhibitory concentrations are in the nanomolar range in the context of immortalized cell lines and human PBMCs. The compound shows high metabolic stability when exposed to human S-9 hepatocyte subcellular fractions. Antiviral activity is host-cell species specific and most pronounced in cells of higher mammalian origin, supporting a host-cell target. While the compound induces a temporary cell cycle arrest, host mRNA and protein biosynthesis are largely unaffected and treated cells maintain full metabolic activity. Viral replication is blocked at a post-entry step and resembles the inhibition profile of a known inhibitor of viral RNA-dependent RNA-polymerase (RdRp) activity. Direct assessment of RdRp activity in the presence of the reagent reveals strong inhibition both in the context of viral infection and in reporter-based minireplicon assays. In toto, we have identified a compound class with broad viral target range that blocks host factors required for viral RdRp activity. Viral adaptation attempts did not induce resistance after prolonged exposure, in contrast to rapid adaptation to a pathogen-directed inhibitor of RdRp activity.
Highlights
Myxoviruses are enveloped, negative-strand RNA viruses that are transmitted through the respiratory route
These studies have underscored the notion that several cellular pathways are exploited for virus replication [45,46], supporting the hypothesis that a host-directed antiviral may enjoy an expanded viral target range, rendering it effective for the treatment of several related viral diseases
Technologies applied for host-directed drug discovery include cDNA and siRNA-based microarray analyses combined with pathway-guided data mining [47,48,49,50,51], loss-of-function screens using aptamers or small oligonucleotides [52,53,54, 55,56,57,58], protein array analyses [59] and chemical library screening [60,61]
Summary
Myxoviruses are enveloped, negative-strand RNA viruses that are transmitted through the respiratory route. Clinical complications associated with some myxoviruses involve persistent infections, the viruses predominantly induce acute respiratory or systemic disease. Myxoviruses are responsible for the majority of human morbidity and mortality due to viral respiratory illness globally [2,3]. Influenza virus is the leading cause of morbidity and mortality from respiratory disease in North America despite the existence of vaccine prophylaxis. This is due to the fact that the vaccines currently in use reduce illness in approximately 70% of healthy adults when homologous to the prevalent circulating virus, but protection in the elderly reaches only approximately 40%. Vaccine efficacy is reduced substantially when the circulating strains differ from those constituting the vaccine [2]
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