title: A novel selective LSD1/KDM1A inhibitor epigenetically blocks herpes simplex virus lytic replication and reactivation from latency.
abstract: Cellular processes requiring access to the DNA genome are regulated by an overlay of epigenetic modifications, including histone modification and chromatin remodeling. Similar to the cellular host, many nuclear DNA viruses that depend upon the host cell's transcriptional machinery are also subject to the regulatory impact of chromatin assembly and modification. Infection of cells with alphaherpesviruses (herpes simplex virus [HSV] and varicella-zoster virus [VZV]) results in the deposition of nucleosomes bearing repressive histone H3K9 methylation on the viral genome. This repressive state is modulated by the recruitment of a cellular coactivator complex containing the histone H3K9 demethylase LSD1 to the viral immediate-early (IE) gene promoters. Inhibition of the activity of this enzyme results in increased repressive chromatin assembly and suppression of viral gene expression during lytic infection as well as reactivation from latency in a mouse ganglion explant model. However, available small-molecule LSD1 inhibitors are not originally designed to inhibit LSD1, but rather monoamine oxidases (MAO) in general. Thus, their specificity for and potency to LSD1 is low. In this study, a novel specific LSD1 inhibitor was identified that potently repressed HSV IE gene expression, genome replication, and reactivation from latency. Importantly, the inhibitor also suppressed primary infection of HSV in vivo in a mouse model. Based on common control of a number of DNA viruses by epigenetic modulation, it was also demonstrated that this LSD1 inhibitor blocks initial gene expression of the human cytomegalovirus and adenovirus type 5. IMPORTANCE Epigenetic mechanisms, including histone modification and chromatin remodeling, play important regulatory roles in all cellular processes requiring access to the genome. These mechanisms are often altered in disease conditions, including various cancers, and thus represent novel targets for drugs. Similarly, many viral pathogens are regulated by an epigenetic overlay that determines the outcome of infection. Therefore, these epigenetic targets also represent novel antiviral targets. Here, a novel inhibitor was identified with high specificity and potency for the histone demethylase LSD1, a critical component of the herpes simplex virus (HSV) gene expression paradigm. This inhibitor was demonstrated to have potent antiviral potential in both cultured cells and animal models. Thus, in addition to clearly demonstrating the critical role of LSD1 in regulation of HSV infection, as well as other DNA viruses, the data extends the therapeutic potential of chromatin modulation inhibitors from the focused field of oncology to the arena of antiviral agents.
authors: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors: Yu
authors: Y
authors: Liang
authors: Debra
authors: D
authors: Quenelle
authors: Jodi L
authors: JL
authors: Vogel
authors: Cristina
authors: C
authors: Mascaro
authors: Alberto
authors: A
authors: Ortega
authors: Thomas M
authors: TM
authors: Kristie
mesh_terms: D000256:Adenoviridae / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D054884:Host-Pathogen Interactions / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018139:Simplexvirus / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology*; D019562:Viral Load; D014775:Virus Activation / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D056466:Histone Demethylases; C495195:KDM1A protein, human
references: Genes Cancer. 2011 Jun;2(6):663-79
references: 21941621
references: PLoS Pathog. 2008 May 23;4(5):e1000071
references: 18497856
references: Antivir Chem Chemother. 2011 Nov 17;22(3):131-7
references: 22095521
references: Cell Res. 2011 Mar;21(3):381-95
references: 21321607
references: Nucleic Acids Res. 2012 Mar;40(6):2369-76
references: 22116065
references: Cell. 2007 Feb 23;128(4):683-92
references: 17320506
references: Adv Exp Med Biol. 2011;711:117-36
references: 21627046
references: Transl Res. 2009 Jan;153(1):4-10
references: 19100952
references: Nat Protoc. 2006;1(2):729-48
references: 17406303
references: J Med Chem. 2011 Dec 22;54(24):8236-50
references: 21955276
references: J Virol. 2004 Feb;78(3):1139-49
references: 14722269
references: Cell. 2007 Feb 23;128(4):707-19
references: 17320508
references: Nat Med. 2009 Nov;15(11):1312-7
references: 19855399
references: Nat Rev Genet. 2011 Apr;12(4):283-93
references: 21358745
references: Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16055-9
references: 16247011
references: J Virol. 2004 Nov;78(22):12508-18
references: 15507638
references: Clin Exp Pharmacol Physiol. 2011 Jul;38(7):451-9
references: 21309809
references: PLoS Pathog. 2010 Jun 03;6(6):e1000935
references: 20532208
references: Chem Biol. 2006 Jun;13(6):563-7
references: 16793513
references: Trends Microbiol. 2006 Mar;14(3):132-40
references: 16458005
references: J Infect Dis. 2010 Nov 15;202(10):1492-9
references: 20923374
references: J Virol. 2012 Oct;86(20):11287-300
references: 22875975
references: Cancer Cell. 2012 Apr 17;21(4):473-87
references: 22464800
references: Antimicrob Agents Chemother. 2011 Oct;55(10):4728-34
references: 21788472
references: Future Oncol. 2009 Dec;5(10):1615-29
references: 20001799
references: Nat Rev Drug Discov. 2009 Sep;8(9):724-32
references: 19721445
references: Biochim Biophys Acta. 2010 Mar-Apr;1799(3-4):286-95
references: 19682613
references: Biochim Biophys Acta. 2010 Mar-Apr;1799(3-4):192-9
references: 19786128
references: Biochim Biophys Acta. 2010 Mar-Apr;1799(3-4):228-35
references: 19853674
references: Lancet Neurol. 2009 Nov;8(11):1056-72
references: 19833297
references: J Virol. 2007 Dec;81(23):13248-53
references: 17881451
references: Sci Transl Med. 2013 Jan 9;5(167):167ra5
references: 23303604
references: Biochemistry. 2007 Apr 10;46(14):4408-16
references: 17367163
references: Nat Med. 2012 Mar 11;18(4):605-11
references: 22406747
references: Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):10835-40
references: 17578910
references: Pharmacol Ther. 2007 Nov;116(2):249-65
references: 17720252
references: Genes Dev. 2003 Apr 1;17(7):896-911
references: 12670868
references: PLoS One. 2012;7(4):e35065
references: 22493729
references: Rev Med Virol. 2010 Jan;20(1):34-50
references: 19890944
references: Curr Cancer Drug Targets. 2009 Dec;9(8):963-81
references: 20025605
references: Biochim Biophys Acta. 2010 Mar-Apr;1799(3-4):246-56
references: 20045093
references: Nature. 2010 Dec 23;468(7327):1119-23
references: 21068722
references: Nat Rev Microbiol. 2008 Mar;6(3):211-21
references: 18264117
references: Int Rev Neurobiol. 2009;89:67-84
references: 19900616
references: Nat Biotechnol. 2010 Oct;28(10):1069-78
references: 20944599
references: J Cell Physiol. 2008 Aug;216(2):295-302
references: 18314879
references: Epigenomics. 2011 Oct;3(5):639-48
references: 22126251
references: Curr Opin Chem Biol. 2010 Aug;14(4):505-10
references: 20621549
references: PLoS One. 2010 Nov 04;5(11):e15416
references: 21079815
references: Biochim Biophys Acta. 2010 Mar-Apr;1799(3-4):236-45
references: 19853673
references: Int J Cancer. 2011 Feb 1;128(3):574-86
references: 20333681
references: Nat Rev Cancer. 2010 Jul;10(7):457-69
references: 20574448
references: Epigenomics. 2011 Oct;3(5):547-65
references: 22126246
references: Drug Discov Today. 2010 Jan;15(1-2):65-70
references: 19897050
references: PLoS Pathog. 2011 Aug;7(8):e1002184
references: 21876670
references: J Virol. 2009 Aug;83(16):8173-81
references: 19515780
references: J Virol. 2006 Feb;80(4):2063-8
references: 16439563