Antiviral Properties of the LSD1 Inhibitor SP-2509.
Animals
Antiviral Agents
/ pharmacology
Cell Line
Chlorocebus aethiops
DNA Replication
/ drug effects
DNA, Viral
Gene Expression Regulation, Viral
/ drug effects
Genes, Immediate-Early
Herpes Simplex
/ drug therapy
Herpesvirus 1, Human
/ drug effects
Histone Demethylases
/ drug effects
Histones
/ metabolism
Humans
Hydrazines
/ pharmacology
Promoter Regions, Genetic
Sulfonamides
/ pharmacology
Vero Cells
Virus Replication
/ drug effects
DNA replication
HSV-1
LSD1
SP-2509
antiviral
herpes simplex virus
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
15 09 2020
15 09 2020
Historique:
received:
18
05
2020
accepted:
16
07
2020
pubmed:
24
7
2020
medline:
22
12
2020
entrez:
24
7
2020
Statut:
epublish
Résumé
Lysine-specific demethylase 1 (LSD1) targets cellular proteins, including histone H3, p53, E2F, and Dnmt1, and is involved in the regulation of gene expression, DNA replication, the cell cycle, and the DNA damage response. LSD1 catalyzes demethylation of histone H3K9 associated with herpes simplex virus 1 (HSV-1) immediate early (IE) promoters and is necessary for IE gene expression, viral DNA replication, and reactivation from latency. We previously found that LSD1 associates with HSV-1 replication forks and replicating viral DNA, suggesting that it may play a direct role in viral replication or coupled processes. We investigated the effects of the LSD1 inhibitor SP-2509 on the HSV-1 life cycle. Unlike previously investigated LSD1 inhibitors tranylcypromine (TCP) and OG-L002, which covalently attach to the LSD1 cofactor flavin adenine dinucleotide (FAD) to inhibit demethylase activity, SP-2509 has previously been shown to inhibit LSD1 protein-protein interactions. We found that SP-2509 does not inhibit HSV-1 IE gene expression or transcription factor and RNA polymerase II (Pol II) association with viral DNA prior to the onset of replication. However, SP-2509 does inhibit viral DNA replication, late gene expression, and virus production. We used EdC labeling of nascent viral DNA to image aberrant viral replication compartments that form in the presence of SP-2509. Treatment resulted in the formation of small replication foci that colocalize with replication proteins but are defective for Pol II recruitment. Taken together, these data highlight a potential new role for LSD1 in the regulation of HSV-1 DNA replication and gene expression after the onset of DNA replication.
Identifiants
pubmed: 32699090
pii: JVI.00974-20
doi: 10.1128/JVI.00974-20
pmc: PMC7495396
pii:
doi:
Substances chimiques
Antiviral Agents
0
DNA, Viral
0
Histones
0
Hydrazines
0
SP2509
0
Sulfonamides
0
Histone Demethylases
EC 1.14.11.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R01 AI030612
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI137652
Pays : United States
Informations de copyright
Copyright © 2020 Harancher et al.
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