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 4

FLS-359 inhibits HCMV spread in fibroblasts.

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FLS-359 inhibits HCMV spread in fibroblasts. (A) Schematic representatio...
(A) Schematic representation of the spread assay. (B and C) Cytotoxicity was assessed in confluent MRC-5 cells after 7 days of FLS-359 treatment by DAPI staining for cell count (B) or neutral red uptake (C) (n = 3). (D and E) Confocal images of MRC-5 cells infected with TB40/E-mCherry-UL99eGFP (0.01 IU/cell) at 7 days post-infection (dpi), treated with vehicle (D) or FLS-359 at 0.5 μM (E). Fluorescent mCherry (red) is expressed with immediate-early kinetics and eGFP (green) with late kinetics, and DAPI (blue) locates nuclei. Scale bars: 300 μm. (F) Virus spread assay. CMV-infected cell area is quantified by mCherry fluorescence and plotted versus FLS-359, ganciclovir (GCV), or letermovir (LMV) concentrations. IC50 (mean ± SD) is reported (n = 4). (G) Virus yield assay. Cell-free virus at 7 dpi was quantified by TCID50. IC50 is reported. LOQ, limit of quantification.