Characterization and structure-activity relationship analysis of a class of antiviral compounds that directly bind dengue virus capsid protein and are incorporated into virions.
Characterization and structure-activity relationship analysis of a class of antiviral compounds that directly bind dengue virus capsid protein and are incorporated into virions.
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DOI：
10.1016/j.antiviral.2018.04.019
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发表时间：
2018-07
影响因子：
7.6
通讯作者：
中科院分区：
文献类型：
--
作者：
登革热病毒（DENV）是热带和亚热带地区的地方性病原体，在世界范围内造成严重的发病率和死亡率。虽然在DENV流行的几个国家正在使用部分有效的疫苗，但没有批准抗病毒治疗用于对抗DENV相关疾病。本文报道了新型DENV复制小分子抑制剂VGTI-A3和VGTI-A3 - 03的特性，并利用化学类似物对分子进行了构效关系分析。VGTI-A3和VGTI-A3 - 03具有高度的病毒特异性，对DENV血清2型具有最大的活性。进一步的分析表明，用VGTI-A3-03处理感染细胞不会抑制病毒RNA复制或病毒颗粒的分泌。相反，与对照细胞分泌的颗粒相比，A3-03处理细胞分泌的颗粒的传染性显著降低。引发的vgti - a3 - 03抗性突变体在衣壳分子的二聚化界面处显示出明显的结合袋。此外，我们发现VGTI-A3-03被整合到从感染细胞释放的病毒颗粒中。总之，这些数据提供了对一类潜在有用的抗denv抑制剂的详细分析，并进一步确定了病毒衣壳蛋白的一个区域，作为其他治疗方法的可药物靶点。
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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影响因子：
6.7
作者：
Blair WS;Pickford C;Irving SL;Brown DG;Anderson M;Bazin R;Cao J;Ciaramella G;Isaacson J;Jackson L;Hunt R;Kjerrstrom A;Nieman JA;Patick AK;Perros M;Scott AD;Whitby K;Wu H;Butler SL
通讯作者：
Butler SL
DOI：
10.1073/pnas.0305892101
发表时间：
2004-03-09
影响因子：
11.1
作者：
Ma, LX;Jones, CT;Post, CB
通讯作者：
Post, CB
影响因子：
5.4
作者：
Courageot, MP;Frenkiel, MP;Desprès, P
通讯作者：
Desprès, P
影响因子：
4.8
作者：
Gurukumar, K. R.;Priyadarshini, D.;Cecilia, D.
通讯作者：
Cecilia, D.
影响因子：
56.9
作者：
Deres, K;Schröder, CH;Rübsamen-Waigmann, H
通讯作者：
Rübsamen-Waigmann, H