Characterization and structure-activity relationship analysis of a class of antiviral compounds that directly bind dengue virus capsid protein and are incorporated into virions

Jessica L. Smith, Kayla Sheridan, Christopher J. Parkins, Lisa Frueh, Adriana L. Jemison, Kathleya Strode, Geoffrey Dow, Aaron Nilsen, Alec Hirsch

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Dengue viruses (DENV) are endemic pathogens of tropical and subtropical regions and cause significant morbidity and mortality worldwide. Although a partially effective vaccine is in use in several countries in which DENV are endemic, no antiviral therapeutics are approved for combating DENV-associated disease. Herein, we report the characterization of novel small molecule inhibitors of DENV replication, VGTI-A3 and VGTI-A3-03, as well as structure-activity relationship analysis of the molecules using a panel of chemical analogs. VGTI-A3 and VGTI-A3-03 are highly virus-specific, with greatest activity against DENV serotype 2. Further analysis revealed that treatment of infected cells with VGTI-A3-03 does not inhibit viral RNA replication or secretion of viral particles. Rather, the infectivity of secreted particles from A3-03 treated cells is significantly diminished compared to particles secreted from control cells. Elicitation of VGTI-A3-03-resistant mutants demonstrated a clear binding pocket in the capsid molecule at the dimerization interface. Additionally, we show that VGTI-A3-03 is incorporated into virus particles released from infected cells. In summary, these data provide detailed analysis of a potentially useful class of anti-DENV inhibitors and further identify a region of the viral capsid protein as a druggable target for other therapeutic approaches.

Original languageEnglish (US)
Pages (from-to)12-19
Number of pages8
JournalAntiviral Research
Volume155
DOIs
StatePublished - Jul 1 2018

Fingerprint

Dengue Virus
Capsid Proteins
Structure-Activity Relationship
Virion
Antiviral Agents
Capsid
Viral RNA
Dimerization
Viral Proteins
Virus Diseases
Virus Replication
Vaccines
Viruses
Morbidity
Mortality
Therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Virology

Cite this

Characterization and structure-activity relationship analysis of a class of antiviral compounds that directly bind dengue virus capsid protein and are incorporated into virions. / Smith, Jessica L.; Sheridan, Kayla; Parkins, Christopher J.; Frueh, Lisa; Jemison, Adriana L.; Strode, Kathleya; Dow, Geoffrey; Nilsen, Aaron; Hirsch, Alec.

In: Antiviral Research, Vol. 155, 01.07.2018, p. 12-19.

Research output: Contribution to journalArticle

Smith, Jessica L. ; Sheridan, Kayla ; Parkins, Christopher J. ; Frueh, Lisa ; Jemison, Adriana L. ; Strode, Kathleya ; Dow, Geoffrey ; Nilsen, Aaron ; Hirsch, Alec. / Characterization and structure-activity relationship analysis of a class of antiviral compounds that directly bind dengue virus capsid protein and are incorporated into virions. In: Antiviral Research. 2018 ; Vol. 155. pp. 12-19.
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