دورية أكاديمية
A Chemical Strategy for Intracellular Arming of an Endogenous Broad-Spectrum Antiviral Nucleotide.
العنوان: | A Chemical Strategy for Intracellular Arming of an Endogenous Broad-Spectrum Antiviral Nucleotide. |
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المؤلفون: | Passow KT; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States., Caldwell HS; Department of Biomedical Sciences, State University of New York at Albany School of Public Health, Albany, New York 12144, United States.; The Arbovirus Laboratory, Wadsworth Center, New York State Department of Health, Slingerlands, New York 12201, United States., Ngo KA; The Arbovirus Laboratory, Wadsworth Center, New York State Department of Health, Slingerlands, New York 12201, United States., Arnold JJ; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, United States., Antczak NM; Department of Health Sciences and Technology, ETH Zürich, Zürich 8092, Switzerland., Narayanan A; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, United States., Jose J; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.; Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, United States., Sturla SJ; Department of Health Sciences and Technology, ETH Zürich, Zürich 8092, Switzerland., Cameron CE; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, United States., Ciota AT; Department of Biomedical Sciences, State University of New York at Albany School of Public Health, Albany, New York 12144, United States.; The Arbovirus Laboratory, Wadsworth Center, New York State Department of Health, Slingerlands, New York 12201, United States., Harki DA; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States. |
المصدر: | Journal of medicinal chemistry [J Med Chem] 2021 Oct 28; Vol. 64 (20), pp. 15429-15439. Date of Electronic Publication: 2021 Oct 18. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
مواضيع طبية MeSH: | Antiviral Agents/*pharmacology , Cytidine Triphosphate/*pharmacology , West Nile virus/*drug effects , Zika Virus/*drug effects, Animals ; Antiviral Agents/chemistry ; Cell Line ; Chlorocebus aethiops ; Cytidine Triphosphate/chemistry ; Dose-Response Relationship, Drug ; Humans ; Microbial Sensitivity Tests ; Molecular Structure ; Structure-Activity Relationship |
مستخلص: | The naturally occurring nucleotide 3'-deoxy-3',4'-didehydro-cytidine-5'-triphosphate ( ddhCTP ) was recently found to exert potent and broad-spectrum antiviral activity. However, nucleoside 5'-triphosphates in general are not cell-permeable, which precludes the direct use of ddhCTP as a therapeutic. To harness the therapeutic potential of this endogenous antiviral nucleotide, we synthesized phosphoramidate prodrug HLB-0532247 ( 1 ) and found it to result in dramatically elevated levels of ddhCTP in cells. We compared 1 and 3'-deoxy-3',4'-didehydro-cytidine ( ddhC ) and found that 1 more effectively reduces titers of Zika and West Nile viruses in cell culture with minimal nonspecific toxicity to host cells. We conclude that 1 is a promising antiviral agent based on a novel strategy of facilitating elevated levels of the endogenous ddhCTP antiviral nucleotide. |
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معلومات مُعتمدة: | P30 CA077598 United States CA NCI NIH HHS; R01 AI045818 United States AI NIAID NIH HHS; R01 GM110129 United States GM NIGMS NIH HHS; R21 AI146856 United States AI NIAID NIH HHS |
المشرفين على المادة: | 0 (3'-deoxy-3',4'-didehydro-CTP) 0 (Antiviral Agents) 65-47-4 (Cytidine Triphosphate) |
تواريخ الأحداث: | Date Created: 20211018 Date Completed: 20211208 Latest Revision: 20221029 |
رمز التحديث: | 20221213 |
مُعرف محوري في PubMed: | PMC8877721 |
DOI: | 10.1021/acs.jmedchem.1c01481 |
PMID: | 34661397 |
قاعدة البيانات: | MEDLINE |
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