Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan.
Pathogen Genomics Center, National Institute for Infectious Diseases, Tokyo 208-0011, Japan.
Viruses. 2022 Apr 15;14(4):816. doi: 10.3390/v14040816.
Lamellarin α 20-sulfate is a cell-impenetrable marine alkaloid that can suppress infection that is mediated by the envelope glycoprotein of human immunodeficiency virus type 1. We explored the antiviral action and mechanisms of this alkaloid against emerging enveloped RNA viruses that use endocytosis for infection. The alkaloid inhibited the infection of retroviral vectors that had been pseudotyped with the envelope glycoprotein of Ebola virus and SARS-CoV-2. The antiviral effects of lamellarin were independent of the retrovirus Gag-Pol proteins. Interestingly, although heparin and dextran sulfate suppressed the cell attachment of vector particles, lamellarin did not. In silico structural analyses of the trimeric glycoprotein of the Ebola virus disclosed that the principal lamellarin-binding site is confined to a previously unappreciated cavity near the NPC1-binding site and fusion loop, whereas those for heparin and dextran sulfate were dispersed across the attachment and fusion subunits of the glycoproteins. Notably, lamellarin binding to this cavity was augmented under conditions where the pH was 5.0. These results suggest that the final action of the alkaloid against Ebola virus is specific to events following endocytosis, possibly during conformational glycoprotein changes in the acidic environment of endosomes. Our findings highlight the unique biological and physicochemical features of lamellarin α 20-sulfate and should lead to the further use of broadly reactive antivirals to explore the structural mechanisms of virus replication.
Lamellarin α 20-硫酸盐是一种细胞不可渗透的海洋生物碱，可抑制人类免疫缺陷病毒 1 的包膜糖蛋白介导的感染。我们探索了这种生物碱对新兴包膜 RNA 病毒的抗病毒作用和机制，这些病毒通过内吞作用感染。该生物碱抑制了用埃博拉病毒和 SARS-CoV-2 的包膜糖蛋白假型化的逆转录病毒载体的感染。Lamellarin 的抗病毒作用与逆转录病毒 Gag-Pol 蛋白无关。有趣的是，尽管肝素和硫酸葡聚糖抑制了载体颗粒的细胞附着，但 Lamellarin 没有。对埃博拉病毒三聚体糖蛋白的计算机结构分析表明，主要的 Lamellarin 结合位点局限于 NPC1 结合位点和融合环附近以前未被重视的腔中，而肝素和硫酸葡聚糖的结合位点则分散在糖蛋白的附着和融合亚基上。值得注意的是，在 pH 值为 5.0 的条件下，Lamellarin 与该腔的结合得到增强。这些结果表明，生物碱对埃博拉病毒的最终作用是针对内吞作用后的事件，可能是在内体的酸性环境中糖蛋白构象变化期间。我们的发现突出了 Lamellarin α 20-硫酸盐的独特生物学和物理化学特性，应导致进一步使用广泛反应性的抗病毒药物来探索病毒复制的结构机制。
