Design, synthesis, and biological evaluation of novel penindolone derivatives as potential inhibitors of hemagglutinin-mediated membrane fusion
Design, synthesis, and biological evaluation of novel penindolone derivatives as potential inhibitors of hemagglutinin-mediated membrane fusion
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DOI：
10.1016/j.ejmech.2023.115615
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发表时间：
2023-07-04
影响因子：
6.7
通讯作者：
Li，Dehai
中科院分区：
文献类型：
--
作者：
Li，Bohan;Huang，Lianghao;Li，Dehai
开发和设计具有新机制的抗流感药物对于对抗甲型流感病毒（IAV）的持续威胁具有重要意义。血凝素（HA）被认为是治疗 IAV 的潜在靶点。我们之前的研究发现了 Penindolone (PND)，一种新的双克拉醇吲哚加合物，作为 HA 靶向先导化合物，具有抗 IAV 活性。为了增强生物活性并了解构效关系（SAR），本研究设计并合成了65种PND衍生物，并系统研究了其抗IAV活性以及HA靶向作用。其中，化合物5g对HA具有高亲和力，在抑制HA介导的膜融合方面比PND更有效。化合物5g可能作用于HA的胰蛋白酶切割位点，对膜融合表现出强烈的抑制作用。此外，口服5g可显着降低IAV感染小鼠肺部病毒滴度，减轻体重减轻，提高存活率，优于PND的效果。这些发现表明HA抑制剂5g有潜力在未来开发成新型广谱抗IAV药物。
Development and design of anti-influenza drugs with novel mechanisms is of great significance to combat the ongoing threat of influenza A virus (IAV). Hemagglutinin (HA) is regarded as a potential target for the therapy of IAV. Our previous research led to the discovery of penindolone (PND), a new diclavatol indole adduct, as an HA targeting leading compound exhibited anti-IAV activity. To enhance the bioactivity and understand the structure-activity relationships (SARs), 65 PND derivatives were designed and synthesized, and the anti-IAV activities as well as the HA targeting effects were systematically investigated in this study. Among them, compound5gpossessed high affinity to HA and was more effective than PND in terms of inhibiting HA-mediated membrane fusion. Compound5gmay act on the trypsin cleavage site of HA to exhibit a strong inhibition on membrane fusion. In addition, oral administration of5gcan significantly reduce the pulmonary virus titer, attenuate the weight loss, and improve the survival of IAV-infected mice, superior to the effects of PND. These findings suggest that the HA inhibitor5ghas potential to be developed into a novel broad-spectrum anti-IAV agent in the future.