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Targeting norovirus infection - Multivalent entry inhibitor design based on NMR experiments

机译：靶向诺如病毒感染-基于NMR实验的多价进入抑制剂设计

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Noroviruses attach to their host cells through histo blood group antigens (HBGAs), and compounds that interfere with this interaction are likely to be of therapeutic or diagnostic interest. It is shown that NMR binding studies can simultaneously identify and differentiate the site for binding HBGA ligands and complementary ligands from a large compound library, thereby facilitating the design of potent heterobifunctional ligands. Saturation transfer difference (STD) NMR experiments, spin-lock filtered NMR experiments, and interligand NOE (ILOE) experiments in the presence of virus-like particles (VLPs), identified compounds that bind to the HBGA binding site of human norovirus. Based on these data two multivalent prototype entry-inhibitors against norovirus infection were synthesized. A surface plasmon resonance based inhibition assay showed avidity gains of 1000 and one million fold over a millimolar univalent ligand. This suggests that further rational design of multivalent inhibitors based on our strategy will identify potent entry-inhibitors against norovirus infections.
机译：诺如病毒通过组织血型抗原（HBGA）附着在其宿主细胞上，干扰这种相互作用的化合物可能具有治疗或诊断意义。结果表明，NMR结合研究可以同时从大型化合物库中识别和区分结合HBGA配体和互补配体的位点，从而有助于设计有效的异双功能配体。在存在病毒样颗粒（VLP）的情况下，饱和转移差异（STD）NMR实验，自旋锁定过滤NMR实验和配体NOE（ILOE）实验确定了与人诺如病毒的HBGA结合位点结合的化合物。基于这些数据，合成了两种针对诺如病毒感染的多价原型进入抑制剂。基于表面等离振子共振的抑制试验显示，亲合力比毫摩尔单价配体增加了1000倍和100万倍。这表明基于我们的策略进一步合理设计多价抑制剂将确定针对诺如病毒感染的有效进入抑制剂。

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