Sirtuin Inhibitors Are Broadly Antiviral against Arboviruses

Abstract

Arthropod-borne viruses are diverse pathogens and are often associated with human disease. These viruses span multiple genera, including flaviviruses, alphaviruses, and bunyaviruses. In a high-throughput drug screen, we found that tenovin-1 was antiviral against the flaviviruses Zika virus and dengue virus. Tenovin-1 is a sirtuin inhibitor, and here we found that inhibition of sirtuins, but not inhibition of the related histone deacetylases, is potently antiviral against diverse arboviruses. Sirtuin inhibitors block infection of arboviruses in multiple human cell types. We found that sirtuin inhibitors arrest infection downstream of entry but that they do so at an early step, preventing the accumulation of viral RNA and protein. However, sirtuin inhibitors had no impact on the replication of flaviviral replicons, suggesting a defect in the establishment of replication. Consistent with this, we found that sirtuin inhibitors impacted double-stranded RNA (dsRNA) accumulation during flaviviral infection. Since these viruses infect vector insects, we also tested whether sirtuin inhibitors impacted infection of adult flies and found that these inhibitors blocked infection; therefore, they target highly conserved facets of replication. Taken together, these results suggest that sirtuin inhibitors represent a new class of potent host-targeting antivirals. IMPORTANCE Arthropod-borne viruses are diverse pathogens and are associated with human disease. Through high-throughput drug screening, we found that sirtuin inhibitors are potently antiviral against diverse arboviruses, including flaviviruses such as West Nile virus, bunyaviruses such as Rift Valley fever virus, and alphaviruses such as chikungunya virus. Sirtuin inhibitors block infection of these viruses in multiple human cell types. Moreover, we found that sirtuin inhibitors arrest infection downstream of entry but that they do so at an early step, preventing the accumulation of viral RNA and protein. Since these viruses infect vector insects, we also tested whether sirtuin inhibitors impacted infection of adult flies and found that these inhibitors blocked infection; therefore, they target highly conserved facets of replication. Taken together, these results suggest that sirtuin inhibitors represent a new class of potent host-targeting antivirals.

Melatonin Inhibits Dengue Virus Infection via the Sirtuin 1-Mediated Interferon Pathway

“…When DENV-infected cells were co-treated with MEL and EX-527, virus replication was significantly restored when compared to MEL treatment alone, suggesting involvement of SIRT1-mediated mechanism in DENV production ( Figure 6 ). Previously, SIRT inhibitors that inhibit both SIRT1 and SIRT2 are known to have antiviral properties in arboviral replication [ 34 ].…”

Antivirals against the Chikungunya Virus

“…Sirtuins (SIRTs) are an evolutionarily conserved family of seven lysine deacetylases (KDACs) and are present in nuclear and cytoplasmic compartments [ 115 ]. Their precise functions in human cells are not fully elucidated, and their impact on viral replications varies not only on the viral pathogen but also on the subgroup of SIRTs itself [ 115 ].…”

“…Sirtuins (SIRTs) are an evolutionarily conserved family of seven lysine deacetylases (KDACs) and are present in nuclear and cytoplasmic compartments [ 115 ]. Their precise functions in human cells are not fully elucidated, and their impact on viral replications varies not only on the viral pathogen but also on the subgroup of SIRTs itself [ 115 ]. Different sirtuin inhibitors, such as tenovin-1 ( Figure 4 ), sodium phenylbutyrate (a pan-KDAC inhibitor, Figure 4 ), and sirtinol (a specific SIRT1 and SIRT2 inhibitor, Figure 4 ) have been reported to inhibit a set of flaviviruses, bunyaviruses, and alphaviruses–including the CHIKV.…”

“…Different sirtuin inhibitors, such as tenovin-1 ( Figure 4 ), sodium phenylbutyrate (a pan-KDAC inhibitor, Figure 4 ), and sirtinol (a specific SIRT1 and SIRT2 inhibitor, Figure 4 ) have been reported to inhibit a set of flaviviruses, bunyaviruses, and alphaviruses–including the CHIKV. Interestingly, the inhibition of only SIRT1/2 was not enough to block the viral infection [ 115 ].…”

Exploring the Sirtuin Functionality in Ageing Through Human Protein Interaction Networks

“…The compounds are effective against the accumulation of dsRNA during the early phase of the viral infection. The sirtinol was able to target the early accumulation of dsRNA during the infection of the cells by West Nile virus Kunjin even 8 h after infection [45]. The inhibition and downregulation of SIRT1 also have an activating effect on the latent oncovirus Kaposi's sarcoma-associated herpesvirus in the immunocompromised patients [46].…”