An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity
Kathryn L. Roche, Stacy Remiszewski, Matthew J. Todd, John L. Kulp III, Liudi Tang, Alison V. Welsh, Ashley P. Barry, Chandrav De, William W. Reiley, Angela Wahl, J. Victor Garcia, Micah A. Luftig, Thomas Shenk, James R. Tonra, Eain A. Murphy, Lillian W. Chiang
Kathryn L. Roche, Stacy Remiszewski, Matthew J. Todd, John L. Kulp III, Liudi Tang, Alison V. Welsh, Ashley P. Barry, Chandrav De, William W. Reiley, Angela Wahl, J. Victor Garcia, Micah A. Luftig, Thomas Shenk, James R. Tonra, Eain A. Murphy, Lillian W. Chiang
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Research Article Infectious disease Virology

An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity

Abstract

Most drugs used to treat viral disease target a virus-coded product. They inhibit a single virus or virus family, and the pathogen can readily evolve resistance. Host-targeted antivirals can overcome these limitations. The broad-spectrum activity achieved by host targeting can be especially useful in combating emerging viruses and for treatment of diseases caused by multiple viral pathogens, such as opportunistic agents in immunosuppressed patients. We have developed a family of compounds that modulate sirtuin 2, an NAD+-dependent deacylase, and now report the properties of a member of that family, FLS-359. Biochemical and x-ray structural studies show that the drug binds to sirtuin 2 and allosterically inhibits its deacetylase activity. FLS-359 inhibits the growth of RNA and DNA viruses, including members of the coronavirus, orthomyxovirus, flavivirus, hepadnavirus, and herpesvirus families. FLS-359 acts at multiple levels to antagonize cytomegalovirus replication in fibroblasts, causing modest reductions in viral RNAs and DNA, together with a much greater reduction in infectious progeny, and it exhibits antiviral activity in humanized mouse models of infection. Our results highlight the potential of sirtuin 2 inhibitors as broad-spectrum antivirals and set the stage for further understanding of how host epigenetic mechanisms impact the growth and spread of viral pathogens.

Authors

Kathryn L. Roche, Stacy Remiszewski, Matthew J. Todd, John L. Kulp III, Liudi Tang, Alison V. Welsh, Ashley P. Barry, Chandrav De, William W. Reiley, Angela Wahl, J. Victor Garcia, Micah A. Luftig, Thomas Shenk, James R. Tonra, Eain A. Murphy, Lillian W. Chiang

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Figure 9

In vivo efficacy of FLS-359.

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In vivo efficacy of FLS-359. (A) Gelfoam/human fibroblast model. MRC-5 c...
(A) Gelfoam/human fibroblast model. MRC-5 cells were infected with TB40/E-mCherry-UL99eGFP (0.05 IU/cell), incubated for 24 hours, harvested, counted, and seeded (1 × 106 cells) into gelfoam plugs. After 3 days of incubation, plugs were implanted subcutaneously on the flanks of CIEA NOG mice. Beginning at 24 hours after implantation, mice were treated with vehicle control (VC; 0.5% methylcellulose + 0.5% Tween-80, p.o., b.i.d.), FLS-359 (50 mg/kg in VC, p.o., b.i.d.), or valganciclovir (GCV; 100 mg/kg in VC, p.o., b.i.d.). After 11 days of treatment, gelfoam plugs were harvested, and virus was quantified by TCID50 assay. *P < 0.03. (B) Human lung-only mouse model. Beginning at 2 hours before infection with TB40/E (4.25 × 105 IU) via direct injection into lung implants, lung-only mice were treated with vehicle control (VC; 0.5% methylcellulose + 0.5% Tween-80 in sterile distilled water, p.o., b.i.d.), FLS-359 (50 mg/kg in VC, p.o., b.i.d.), or ganciclovir (GCV; 100 mg/kg in VC, i.p., daily). After 17 days of treatment, implants were harvested and processed for TCID50 determination. *P < 0.04. Variance was calculated by 1-sided Kruskal-Wallis test followed by Dunn’s multiple-comparison test.