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Antiviral Res. 2018 Jul;155:12-19. doi: 10.1016/j.antiviral.2018.04.019. Epub 2018 Apr 27.

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

Author information

1
Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, USA.
2
Department of Chemistry, Reed College, Portland, OR, USA.
3
60° Pharmaceuticals LLC, Washington, DC, USA.
4
Medicinal Chemistry Core, Oregon Health & Science University, Portland, OR, USA.
5
Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, USA. Electronic address: hirschal@ohsu.edu.

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.

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