Inhibition of dengue virus replication by a class of small-molecule compounds that antagonize dopamine receptor d4 and downstream mitogen-activated protein kinase signaling Journal Article

   

Authors:	Smith, J. L.; Stein, D. A.; Shum, D.; Fischer, M. A.; Radu, C.; Bhinder, B.; Djaballah, H.; Nelson, J. A.; Früh, K.; Hirsch, A. J.
Article Title:	Inhibition of dengue virus replication by a class of small-molecule compounds that antagonize dopamine receptor d4 and downstream mitogen-activated protein kinase signaling
Abstract:	Dengue viruses (DENV) are endemic pathogens of tropical and subtropical regions that cause significant morbidity and mortality worldwide. To date, no vaccines or antiviral therapeutics have been approved for combating DENV-associated disease. In this paper, we describe a class of tricyclic small-molecule compounds-dihydrodibenzothiepines (DHBTs), identified through highthroughput screening-with potent inhibitory activity against DENV serotype 2. SKI-417616, a highly active representative of this class, displayed activity against all four serotypes of DENV, as well as against a related flavivirus, West Nile virus (WNV), and an alphavirus, Sindbis virus (SINV). This compound was characterized to determine its mechanism of antiviral activity. Investigation of the stage of the viral life cycle affected revealed that an early event in the life cycle is inhibited. Due to the structural similarity of the DHBTs to known antagonists of the dopamine and serotonin receptors, we explored the roles of two of these receptors, serotonin receptor 2A (5HTR2A) and the D4 dopamine receptor (DRD4), in DENV infection. Antagonism of DRD4 and subsequent downstream phosphorylation of epidermal growth factor receptor (EGFR)-related kinase (ERK) were found to impact DENV infection negatively, and blockade of signaling through this network was confirmed as the mechanism of anti- DENV activity for this class of compounds. © 2014, American Society for Microbiology.
Keywords:	signal transduction; mitogen activated protein kinase; controlled study; unclassified drug; drug structure; enzyme activation; drug effect; enzyme phosphorylation; drug mechanism; serotonin antagonist; antivirus agent; virus replication; ic 50; west nile flavivirus; antiviral activity; virus attachment; growth inhibition; life cycle; virogenesis; virus entry; drug identification; dengue; dopamine receptor blocking agent; sindbis virus; priority journal; article; 7 fluoro 11 (4 methylpiperazin 1 yl) 10,11 dihydrodibenzo[b,f]thiepin 2 ol; dopamine 4 receptor; serotonin 2a receptor; ski 417616; dengue virus 2
Journal Title:	Journal of Virology
Volume:	88
Issue:	10
ISSN:	0022-538X
Publisher:	American Society for Microbiology
Date Published:	2014-05-01
Start Page:	5533
End Page:	5542
Language:	English
DOI:	10.1128/jvi.00365-14
PROVIDER:	scopus
PMCID:	PMC4019099
PUBMED:	24599995
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84899047230&partnerID=40&md5=e9c86622683cc8b4474373d822dd29d3
Notes:	J. Virol. -- Export Date: 2 June 2014 -- CODEN: JOVIA -- Source: Scopus

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