Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA.
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA.
Life Sci Alliance. 2020 Jul 1;3(8). doi: 10.26508/lsa.202000724. Print 2020 Aug.
HA plays a critical role in influenza infection and, thus HA is a potential target for antivirals. Recently, our laboratories have described a novel fusion inhibitor, termed CBS1117, with EC ∼3 μM against group 1 HA. In this work, we characterize the binding properties of CBS1117 to avian H5 HA by x-ray crystallography, NMR, and mutagenesis. The x-ray structure of the complex shows that the compound binds near the HA fusion peptide, a region that plays a critical role in HA-mediated fusion. NMR studies demonstrate binding of CBS1117 to H5 HA in solution and show extensive hydrophobic contacts between the compound and HA surface. Mutagenesis studies further support the location of the compound binding site proximal to the HA fusion peptide and identify additional amino acids that are important to compound binding. Together, this work gives new insights into the CBS1117 mechanism of action and can be exploited to further optimize this compound and better understand the group specific activity of small-molecule inhibitors of HA-mediated entry.
HA 在流感感染中起着关键作用，因此 HA 是抗病毒药物的潜在靶点。最近，我们的实验室描述了一种新型融合抑制剂，称为 CBS1117，对组 1 HA 的 EC₅₀为 3 μM。在这项工作中，我们通过 X 射线晶体学、NMR 和诱变来描述 CBS1117 与禽 H5 HA 的结合特性。复合物的 X 射线结构显示，该化合物结合在 HA 融合肽附近，该区域在 HA 介导的融合中起着关键作用。NMR 研究表明，CBS1117 在溶液中与 H5 HA 结合，并显示化合物与 HA 表面之间存在广泛的疏水接触。突变研究进一步支持化合物结合位点靠近 HA 融合肽的位置，并确定了对化合物结合很重要的其他氨基酸。总之，这项工作为 CBS1117 的作用机制提供了新的见解，并可用于进一步优化该化合物，并更好地理解小分子抑制剂对 HA 介导进入的组特异性活性。
