TY - JOUR
T1 - Characterization and structure-activity relationship analysis of a class of antiviral compounds that directly bind dengue virus capsid protein and are incorporated into virions
AU - Smith, Jessica L.
AU - Sheridan, Kayla
AU - Parkins, Christopher J.
AU - Frueh, Lisa
AU - Jemison, Adriana L.
AU - Strode, Kathleya
AU - Dow, Geoffrey
AU - Nilsen, Aaron
AU - Hirsch, Alec J.
N1 - Funding Information:
Analytical support was provided by the Bioanalytical Shared Resource/Pharmacokinetics Core Facility that is part of the University Shared Resource Program at Oregon Health and Sciences University. This work was supported by the NIAID Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (grant U54 AI 081680), the Antiviral Drug Discovery and Development Center (a NIAID Center of Excellence for Translational Research, grant U19 AI 109680), and 60° Pharmaceuticals, LLC.
Funding Information:
Analytical support was provided by the Bioanalytical Shared Resource/Pharmacokinetics Core Facility that is part of the University Shared Resource Program at Oregon Health and Sciences University . This work was supported by the NIAID Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (grant U54 AI 081680 ), the Antiviral Drug Discovery and Development Center (a NIAID Center of Excellence for Translational Research, grant U19 AI 109680 ), and 60° Pharmaceuticals, LLC . Appendix A
PY - 2018/7
Y1 - 2018/7
N2 - 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.
AB - 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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U2 - 10.1016/j.antiviral.2018.04.019
DO - 10.1016/j.antiviral.2018.04.019
M3 - Article
C2 - 29709563
AN - SCOPUS:85046375483
VL - 155
SP - 12
EP - 19
JO - Antiviral Research
JF - Antiviral Research
SN - 0166-3542
ER -