دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity.
المؤلفون: Roche KL; Evrys Bio LLC, Pennsylvania Biotechnology Center, Doylestown, Pennsylvania, USA., Remiszewski S; Evrys Bio LLC, Pennsylvania Biotechnology Center, Doylestown, Pennsylvania, USA., Todd MJ; Evrys Bio LLC, Pennsylvania Biotechnology Center, Doylestown, Pennsylvania, USA., Kulp JL 3rd; Evrys Bio LLC, Pennsylvania Biotechnology Center, Doylestown, Pennsylvania, USA., Tang L; Evrys Bio LLC, Pennsylvania Biotechnology Center, Doylestown, Pennsylvania, USA., Welsh AV; Evrys Bio LLC, Pennsylvania Biotechnology Center, Doylestown, Pennsylvania, USA., Barry AP; Department of Molecular Genetics and Microbiology, Duke Center for Virology, Duke University School of Medicine, Durham, North Carolina, USA., De C; International Center for the Advancement of Translational Science, Division of Infectious Diseases, Center for AIDS Research, University of North Carolina, School of Medicine, Chapel Hill, North Carolina, USA., Reiley WW; TICRO Bioservices, Trudeau Institute, Saranac Lake, New York, USA., Wahl A; International Center for the Advancement of Translational Science, Division of Infectious Diseases, Center for AIDS Research, University of North Carolina, School of Medicine, Chapel Hill, North Carolina, USA., Garcia JV; International Center for the Advancement of Translational Science, Division of Infectious Diseases, Center for AIDS Research, University of North Carolina, School of Medicine, Chapel Hill, North Carolina, USA., Luftig MA; Department of Molecular Genetics and Microbiology, Duke Center for Virology, Duke University School of Medicine, Durham, North Carolina, USA., Shenk T; Evrys Bio LLC, Pennsylvania Biotechnology Center, Doylestown, Pennsylvania, USA.; Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA., Tonra JR; Evrys Bio LLC, Pennsylvania Biotechnology Center, Doylestown, Pennsylvania, USA., Murphy EA; Evrys Bio LLC, Pennsylvania Biotechnology Center, Doylestown, Pennsylvania, USA.; Microbiology and Immunology Department, SUNY Upstate Medical University, Syracuse, New York, USA., Chiang LW; Evrys Bio LLC, Pennsylvania Biotechnology Center, Doylestown, Pennsylvania, USA.
المصدر: The Journal of clinical investigation [J Clin Invest] 2023 Jun 15; Vol. 133 (12). Date of Electronic Publication: 2023 Jun 15.
نوع المنشور: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
مواضيع طبية MeSH: Coronavirus* , Coronavirus Infections*, Animals ; Mice ; Antiviral Agents/pharmacology ; Sirtuin 2/genetics ; RNA, Viral
مستخلص: 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.
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معلومات مُعتمدة: R43 AI110048 United States AI NIAID NIH HHS; R43 AI114079 United States AI NIAID NIH HHS; R01 CA140337 United States CA NCI NIH HHS; R44 AI114079 United States AI NIAID NIH HHS; R44 AI122488 United States AI NIAID NIH HHS
فهرسة مساهمة: Keywords: Drug therapy; Epigenetics; Infectious disease; Structural biology; Virology
المشرفين على المادة: 0 (Antiviral Agents)
EC 3.5.1.- (Sirtuin 2)
0 (RNA, Viral)
تواريخ الأحداث: Date Created: 20230615 Date Completed: 20230616 Latest Revision: 20240127
رمز التحديث: 20240127
مُعرف محوري في PubMed: PMC10266789
DOI: 10.1172/JCI158978
PMID: 37317966
قاعدة البيانات: MEDLINE
الوصف
تدمد:1558-8238
DOI:10.1172/JCI158978