Unité de Génétique Moléculaire des Virus à ARN, Département de Virologie, Institut Pasteur, 75015 Paris, France.
UMR 3569, Centre National de la Recherche Scientifique (CNRS), 75015 Paris, France.
Proc Natl Acad Sci U S A. 2019 May 28;116(22):10968-10977. doi: 10.1073/pnas.1901214116. Epub 2019 May 10.
New therapeutic strategies targeting influenza are actively sought due to limitations in current drugs available. Host-directed therapy is an emerging concept to target host functions involved in pathogen life cycles and/or pathogenesis, rather than pathogen components themselves. From this perspective, we focused on an essential host partner of influenza viruses, the RED-SMU1 splicing complex. Here, we identified two synthetic molecules targeting an α-helix/groove interface essential for RED-SMU1 complex assembly. We solved the structure of the SMU1 N-terminal domain in complex with RED or bound to one of the molecules identified to disrupt this complex. We show that these compounds inhibiting RED-SMU1 interaction also decrease endogenous RED-SMU1 levels and inhibit viral mRNA splicing and viral multiplication, while preserving cell viability. Overall, our data demonstrate the potential of RED-SMU1 destabilizing molecules as an antiviral therapy that could be active against a wide range of influenza viruses and be less prone to drug resistance.
由于现有药物的局限性，人们正在积极寻找针对流感的新治疗策略。宿主定向治疗是一种新兴的概念，旨在针对参与病原体生命周期和/或发病机制的宿主功能，而不是针对病原体本身。从这个角度来看，我们专注于流感病毒的一个重要宿主伙伴，即 RED-SMU1 剪接复合物。在这里，我们鉴定了两种针对 RED-SMU1 复合物组装所必需的α-螺旋/凹槽界面的合成分子。我们解析了 SMU1 N 端结构域与 RED 或与鉴定出的一种破坏该复合物的分子结合的复合物结构。我们表明，这些抑制 RED-SMU1 相互作用的化合物也降低了内源性 RED-SMU1 水平，并抑制了病毒 mRNA 剪接和病毒复制，同时保持细胞活力。总体而言，我们的数据表明，RED-SMU1 不稳定化分子作为一种抗病毒疗法具有潜力，可针对广泛的流感病毒，并降低耐药性的风险。
