Hollmann Axel, Gonçalves Sónia, Augusto Marcelo T, Castanho Miguel A R B, Lee Benhur, Santos Nuno C
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nanomedicine. 2015 Jul;11(5):1163-7. doi: 10.1016/j.nano.2015.02.014. Epub 2015 Mar 17.
Targeting membranes of enveloped viruses represents an exciting new paradigm to explore on the development of broad-spectrum antivirals. Recently, broad-spectrum small-molecule antiviral drugs were described, preventing enveloped virus entry at an intermediate step, after virus binding but before virus-cell fusion. Those compounds, including an oxazolidine-2,4-dithione named JL103 that presented the most promissing results, act deleteriously on the virus envelope but not at the cell membrane level. In this work, by using atomic force microscopy (AFM), we aimed at unraveling the effects that JL103 is able to induce in the lipid membrane architecture at the nanoscale. Our results indicate that singlet oxygen produced by JL103 decreases membrane thickness, with an expansion of the area per phospholipid, by attacking the double bonds of unsaturated phospholipids. This membrane reorganization prevents the fusion between enveloped virus and target cell membranes, resulting in viral entry inhibition.
The recent development of a family of innovative broad-spectrum small-molecule antiviral drugs that block virus cell entry has provided exciting armors against viruses. In this research paper, the authors utilize atomic force microscopy to investigate the mechanism of action of viral blockade. The findings have resulted in new understanding of cell membrane behavior, which may help in further drug design.
靶向包膜病毒的膜代表了探索广谱抗病毒药物开发的一个令人兴奋的新范例。最近，人们描述了广谱小分子抗病毒药物，这些药物在病毒结合后但在病毒-细胞融合前的中间步骤阻止包膜病毒进入。这些化合物，包括一种名为JL103的恶唑烷-2,4-二硫酮，其表现出最有前景的结果，对病毒包膜有有害作用，但对细胞膜水平无影响。在这项工作中，我们使用原子力显微镜（AFM），旨在揭示JL103在纳米尺度上对脂质膜结构能够诱导的影响。我们的结果表明，JL103产生的单线态氧通过攻击不饱和磷脂的双键降低了膜厚度，同时每个磷脂的面积增大。这种膜重组阻止了包膜病毒与靶细胞膜之间的融合，从而导致病毒进入受到抑制。
最近开发的一类创新的广谱小分子抗病毒药物可阻断病毒进入细胞，这为对抗病毒提供了令人兴奋的手段。在这篇研究论文中，作者利用原子力显微镜研究病毒阻断的作用机制。这些发现使人们对细胞膜行为有了新的认识，这可能有助于进一步的药物设计。
