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
PY - 2018/7/1
Y1 - 2018/7/1
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 -