An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity
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 i...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2023-06-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI158978 |
| _version_ | 1797634452339294208 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Kathryn L. Roche |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:09:02Z |
| format | Article |
| id | doaj.art-aae26d7a4a0143a6b97410639780fe44 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:02Z |
| publishDate | 2023-06-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-aae26d7a4a0143a6b97410639780fe442023-11-07T16:20:29ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-06-0113312An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activityKathryn L. RocheStacy RemiszewskiMatthew J. ToddJohn L. Kulp IIILiudi TangAlison V. WelshAshley P. BarryChandrav DeWilliam W. ReileyAngela WahlJ. Victor GarciaMicah A. LuftigThomas ShenkJames R. TonraEain A. MurphyLillian W. ChiangMost 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.https://doi.org/10.1172/JCI158978Infectious diseaseVirology |
| spellingShingle | 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 An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity The Journal of Clinical Investigation Infectious disease Virology |
| title | An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity |
| title_full | An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity |
| title_fullStr | An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity |
| title_full_unstemmed | An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity |
| title_short | An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity |
| title_sort | allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad spectrum antiviral activity |
| topic | Infectious disease Virology |
| url | https://doi.org/10.1172/JCI158978 |
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