Johansson Susanne, Nilsson Emma, Qian Weixing, Guilligay Delphine, Crepin Thibaut, Cusack Stephen, Arnberg Niklas, Elofsson Mikael
Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
J Med Chem. 2009 Jun 25;52(12):3666-78. doi: 10.1021/jm801609s.
The adenovirus serotype Ad37 binds to and infects human corneal epithelial (HCE) cells through attachment to cellular glycoproteins carrying terminal sialic acids. By use of the crystallographic structure of the sialic acid-interacting domain of the Ad37 fiber protein in complex with sialyllactose, a set of N-acyl modified sialic acids were designed to improve binding affinity through increased hydrophobic interactions. These N-acyl modified sialic acids and their corresponding multivalent human serum albumin (HSA) conjugates were synthesized and tested in Ad37 cell binding and cell infectivity assays. Compounds bearing small substituents were as effective inhibitors as sialic acid. X-ray crystallography and overlays with the Ad37-sialyllactose complex showed that the N-acyl modified sialic acids were positioned in the same orientation as sialic acid. Their multivalent counterparts achieved a strong multivalency effect and were more effective to prevent infection than the monomers. Unfortunately, they were less active as inhibitors than multivalent sialic acid.
腺病毒血清型Ad37通过附着于携带末端唾液酸的细胞糖蛋白来结合并感染人角膜上皮（HCE）细胞。利用Ad37纤维蛋白的唾液酸相互作用结构域与唾液乳糖复合物的晶体结构，设计了一组N-酰基修饰的唾液酸，通过增加疏水相互作用来提高结合亲和力。合成了这些N-酰基修饰的唾液酸及其相应的多价人血清白蛋白（HSA）缀合物，并在Ad37细胞结合和细胞感染性试验中进行了测试。带有小取代基的化合物作为抑制剂与唾液酸一样有效。X射线晶体学以及与Ad37-唾液乳糖复合物的叠加显示，N-酰基修饰的唾液酸与唾液酸的定位方向相同。它们的多价对应物实现了强大的多价效应，并且在预防感染方面比单体更有效。不幸的是，它们作为抑制剂的活性不如多价唾液酸。
