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 high-throughput 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.
  
  
  OBJECTIVE
  The dengue viruses are mosquito-borne, reemerging human pathogens that are the etiological agents of a spectrum of febrile diseases. Currently, there are no approved therapeutic treatments for dengue-associated disease, nor is there a vaccine. This study identifies a small molecule, SKI-417616, with potent anti-dengue virus activity. Further analysis revealed that SKI-417616 acts through antagonism of the host cell dopamine D4 receptor and subsequent repression of the ERK phosphorylation pathway. These results suggest that SKI-417616, or other compounds targeting the same cellular pathways, may have therapeutic potential for the treatment of dengue virus infections.
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Sciences University, Beaverton, Oregon, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Smith
authors.forename: David A
authors.initials: DA
authors.lastname: Stein
authors.forename: David
authors.initials: D
authors.lastname: Shum
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Fischer
authors.forename: Constantin
authors.initials: C
authors.lastname: Radu
authors.forename: Bhavneet
authors.initials: B
authors.lastname: Bhinder
authors.forename: Hakim
authors.initials: H
authors.lastname: Djaballah
authors.forename: Jay A
authors.initials: JA
authors.lastname: Nelson
authors.forename: Klaus
authors.initials: K
authors.lastname: Früh
authors.forename: Alec J
authors.initials: AJ
authors.lastname: Hirsch
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism*; D003716:Dengue Virus / Q000187:drug effects* / Q000502:physiology*; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D012845:Sindbis Virus / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects*; D014902:West Nile virus / Q000187:drug effects / Q000502:physiology
chemical_list: D000998:Antiviral Agents; C493599:DRD4 protein, human; D050638:Receptors, Dopamine D4; D020928:Mitogen-Activated Protein Kinases