Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
Antiviral Res. 2013 Oct;100(1):238-45. doi: 10.1016/j.antiviral.2013.08.013. Epub 2013 Aug 28.
Antibody-dependent enhancement (ADE) is thought to play a critical role in the exacerbation of dengue virus (DENV)-induced disease during a heterologous re-infection. Despite ADE's clinical impact, only a few antiviral compounds have been assessed for their anti-ADE activity. We reported earlier that SA-17, a doxorubicin derivative, efficiently inhibits the in vitro infection of DENV and yellow fever virus. Here we explored SA-17's mechanism of inhibition and investigated if the compound is active against ADE of DENV infection. Since enhanced infectivity stimulated by antibodies has been observed with standard and immature DENV, both types of virions were included in the study. We observed that SA-17 (i) inhibits DENV infection by preventing binding/entry to the cell and (ii) interferes with antibody-mediated infection of both standard and immature DENV2. SA-17 markedly reduced the infectivity of DENV2 in ADE conditions, with IC50s ranging from 0.26 to 2.89μM. The compound exerted its activity when added before, during, and after antibody-opsonization of standard and immature virus. Thus, molecules with the characteristics of SA-17 may be attractive antiviral agents since they can be used both to block DENV2 entry during primary and secondary infection and to inhibit ADE of standard and immature virus.
抗体依赖的增强作用（ADE）被认为在登革热病毒（DENV）异源再感染时加剧疾病中起关键作用。尽管 ADE 具有临床影响，但只有少数几种抗病毒化合物被评估其抗 ADE 活性。我们之前报道过，多柔比星衍生物 SA-17 能有效地抑制 DENV 和黄热病毒的体外感染。在这里，我们探讨了 SA-17 的抑制机制，并研究了该化合物是否对 DENV 感染的 ADE 具有活性。由于标准和不成熟的 DENV 都观察到了抗体刺激的增强感染性，因此研究中包括了这两种类型的病毒粒子。我们观察到，SA-17（i）通过阻止与细胞的结合/进入来抑制 DENV 感染，（ii）干扰标准和不成熟 DENV2 的抗体介导的感染。SA-17 明显降低了 ADE 条件下 DENV2 的感染性，IC50 值范围为 0.26 至 2.89μM。该化合物在标准和不成熟病毒的抗体调理前后加入时都发挥了其活性。因此，具有 SA-17 特征的分子可能是有吸引力的抗病毒剂，因为它们可用于阻断原发性和继发性感染期间 DENV2 的进入，并抑制标准和不成熟病毒的 ADE。
