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A Small Covalent Allosteric Inhibitor of Human Cytomegalovirus DNA Polymerase Subunit Interactions.

التفاصيل البيبلوغرافية
العنوان: A Small Covalent Allosteric Inhibitor of Human Cytomegalovirus DNA Polymerase Subunit Interactions.
المؤلفون: Chen H; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 250 Longwood Avenue, Boston, Massachusetts 02115, United States., Coseno M; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 250 Longwood Avenue, Boston, Massachusetts 02115, United States., Ficarro SB; Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute , 450 Brookline Avenue, Boston, Massachusetts 02215, United States., Mansueto MS; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 250 Longwood Avenue, Boston, Massachusetts 02115, United States., Komazin-Meredith G; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 250 Longwood Avenue, Boston, Massachusetts 02115, United States., Boissel S; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 250 Longwood Avenue, Boston, Massachusetts 02115, United States., Filman DJ; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 250 Longwood Avenue, Boston, Massachusetts 02115, United States., Marto JA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 250 Longwood Avenue, Boston, Massachusetts 02115, United States.; Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute , 450 Brookline Avenue, Boston, Massachusetts 02215, United States., Hogle JM; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 250 Longwood Avenue, Boston, Massachusetts 02115, United States., Coen DM; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 250 Longwood Avenue, Boston, Massachusetts 02115, United States.
المصدر: ACS infectious diseases [ACS Infect Dis] 2017 Feb 10; Vol. 3 (2), pp. 112-118. Date of Electronic Publication: 2016 Dec 06.
نوع المنشور: Letter; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: ACS Publications Country of Publication: United States NLM ID: 101654580 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2373-8227 (Electronic) Linking ISSN: 23738227 NLM ISO Abbreviation: ACS Infect Dis Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : ACS Publications, [2015]-
مواضيع طبية MeSH: Antiviral Agents/*pharmacology , Cytomegalovirus/*enzymology , DNA-Binding Proteins/*metabolism , DNA-Directed DNA Polymerase/*metabolism , Small Molecule Libraries/*pharmacology , Viral Proteins/*metabolism, Allosteric Regulation ; Allosteric Site ; Antiviral Agents/chemistry ; Crystallography, X-Ray ; DNA-Binding Proteins/chemistry ; DNA-Directed DNA Polymerase/chemistry ; High-Throughput Screening Assays ; Humans ; Lysine/metabolism ; Models, Molecular ; Protein Binding/drug effects ; Protein Conformation ; Small Molecule Libraries/chemistry ; Viral Proteins/chemistry
مستخلص: Human cytomegalovirus DNA polymerase comprises a catalytic subunit, UL54, and an accessory subunit, UL44, the interaction of which may serve as a target for the development of new antiviral drugs. Using a high-throughput screen, we identified a small molecule, (5-((dimethylamino)methylene-3-(methylthio)-6,7-dihydrobenzo[c]thiophen-4(5H)-one), that selectively inhibits the interaction of UL44 with a UL54-derived peptide in a time-dependent manner, full-length UL54, and UL44-dependent long-chain DNA synthesis. A crystal structure of the compound bound to UL44 revealed a covalent reaction with lysine residue 60 and additional noncovalent interactions that cause steric conflicts that would prevent the UL44 connector loop from interacting with UL54. Analyses of the reaction of the compound with model substrates supported a resonance-stabilized conjugation mechanism, and substitution of the lysine reduced the ability of the compound to inhibit UL44-UL54 peptide interactions. This novel covalent inhibitor of polymerase subunit interactions may serve as a starting point for new, needed drugs to treat human cytomegalovirus infections.
References: Science. 2015 Jun 5;348(6239):1106-12. (PMID: 26045430)
Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1456-60. (PMID: 7878000)
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14223-8. (PMID: 14623981)
J Virol. 2004 Sep;78(17):9084-92. (PMID: 15308704)
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12396-401. (PMID: 14519856)
J Virol. 1995 Apr;69(4):2047-57. (PMID: 7884850)
Acta Crystallogr D Biol Crystallogr. 2004 Aug;60(Pt 8):1355-63. (PMID: 15272157)
Methods Enzymol. 1997;276:307-26. (PMID: 27754618)
Virus Res. 1994 Dec;34(3):191-206. (PMID: 7856311)
Chem Biol. 2014 Sep 18;21(9):1102-14. (PMID: 25237857)
Cell. 1996 Oct 18;87(2):297-306. (PMID: 8861913)
Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11116-21. (PMID: 18678908)
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55. (PMID: 15299926)
J Virol. 1992 Jul;66(7):4126-33. (PMID: 1318399)
J Virol. 2004 Jan;78(1):158-67. (PMID: 14671097)
Nat Chem Biol. 2016 Nov;12(11):931-936. (PMID: 27595327)
Mol Cell. 2000 Feb;5(2):267-78. (PMID: 10882068)
J Virol. 1993 Dec;67(12):6979-88. (PMID: 8230421)
Chem Biol. 2007 Oct;14(10):1186-97. (PMID: 17961830)
Nat Rev Drug Discov. 2011 Apr;10(4):307-17. (PMID: 21455239)
Virology. 1983 Jan 30;124(2):221-31. (PMID: 6186074)
Chem Biol. 2004 May;11(5):647-54. (PMID: 15157875)
Chem Biol. 2006 Feb;13(2):191-200. (PMID: 16492567)
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32. (PMID: 15572765)
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. (PMID: 20124702)
J Biol Chem. 2006 Feb 24;281(8):5224-32. (PMID: 16371349)
Annu Rev Pharmacol Toxicol. 2014;54:435-56. (PMID: 24160698)
J Virol. 2003 Aug;77(15):8336-44. (PMID: 12857903)
Mol Cell. 2004 Jul 23;15(2):233-44. (PMID: 15260974)
معلومات مُعتمدة: R01 AI019838 United States AI NIAID NIH HHS; R56 AI019838 United States AI NIAID NIH HHS; U54 AI057158 United States AI NIAID NIH HHS
فهرسة مساهمة: Keywords: DNA polymerase; SGM8; covalent inhibitor; human cytomegalovirus; protein−protein interaction
المشرفين على المادة: 0 (Antiviral Agents)
0 (DNA-Binding Proteins)
0 (ICP36 protein, Cytomegalovirus)
0 (Small Molecule Libraries)
0 (UL54 protein, Human herpesvirus 5)
0 (Viral Proteins)
EC 2.7.7.7 (DNA-Directed DNA Polymerase)
K3Z4F929H6 (Lysine)
تواريخ الأحداث: Date Created: 20170211 Date Completed: 20180309 Latest Revision: 20230106
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC5480311
DOI: 10.1021/acsinfecdis.6b00079
PMID: 28183184
قاعدة البيانات: MEDLINE
الوصف
تدمد:2373-8227
DOI:10.1021/acsinfecdis.6b00079