There are a limited number of effective vaccines against dengue virus (DENV) and significant efforts are being made to develop potent anti-virals. Previously, we described that platelet-chemokine CXCL4 negatively regulates interferon (IFN)-α/β synthesis and promotes DENV2 replication. An antagonist to CXCR3 (CXCL4 receptor) reversed it and inhibited viral replication. In a concurrent search, we identified CXCR3-antagonist from our compound library, namely 7D, which inhibited all serotypes of DENV in vitro. With a half-life of ~2.85 h in plasma and no significant toxicity, 7D supplementation (8 mg/kg-body-weight) to DENV2-infected IFNα/β/γR-/-AG129 or wild-type C57BL6 mice increased synthesis of IFN-α/β and IFN-λ, and rescued disease symptoms like thrombocytopenia, leukopenia and vascular-leakage, with improved survival. 7D, having the property to inhibit Sirt-1 deacetylase, promoted acetylation and phosphorylation of STAT3, which in-turn increased plasmablast proliferation, germinal-center maturation and synthesis of neutralizing-antibodies against DENV2 in mice. A STAT3-inhibitor successfully inhibited these effects of 7D. Together, these observations identify compound 7D as a stimulator of IFN-α/β/λ synthesis via CXCL4:CXCR3:p38:IRF3 signaling, and a booster for neutralizing-antibody generation by promoting STAT3-acetylation in plasmablasts, capable of protecting dengue infection.

中文翻译：

---

7D 是一种小分子，通过分别通过 CXCL4：CXCR3：p38：IRF3 和 Sirt1：STAT3 轴增加干扰素和中和抗体来抑制登革热感染。


针对登革热病毒 （DENV） 的有效疫苗数量有限，目前正在做出重大努力来开发有效的抗病毒药物。以前，我们描述了血小板趋化因子 CXCL4 负向调节干扰素 （IFN）-α/β 合成并促进 DENV2 复制。CXCR3 拮抗剂 （CXCL4 receptor） 可逆转 CXCR3 并抑制病毒复制。在同时搜索中，我们从我们的化合物库中鉴定了 CXCR3 拮抗剂，即 7D，它在体外抑制了 DENV 的所有血清型。在血浆中半衰期为 ~2.85 小时且无明显毒性，向 DENV2 感染的 IFNα/β/γR-/-AG129 或野生型 C57BL6 小鼠补充 7D（8 mg/kg-体重）增加了 IFN-α/β 和 IFN-λ 的合成，并挽救了血小板减少症、白细胞减少症和血管渗漏等疾病症状，提高了生存率。7D 具有抑制 Sirt-1 脱乙酰酶的特性，促进 STAT3 的乙酰化和磷酸化，进而增加小鼠浆母细胞增殖、生发中心成熟和抗 DENV2 中和抗体的合成。STAT3 抑制剂成功抑制了 7D 的这些作用。总之，这些观察结果确定化合物 7D 是通过 CXCL4：CXCR3：p38：IRF3 信号合成 IFN-α/β/λ 的刺激剂，并且通过促进浆母细胞中的 STAT3-乙酰化来促进中和抗体的产生，能够保护登革热感染。