Singh S, Jedrzejas M J, Air G M, Luo M, Laver W G, Brouillette W J
Department of Chemistry, University of Alabama at Birmingham 35294, USA.
J Med Chem. 1995 Aug 18;38(17):3217-25. doi: 10.1021/jm00017a005.
Influenza virus sialidase is a surface enzyme that is essential for infection of the virus. The catalytic site is highly conserved among all known influenza variants, suggesting that this protein is a suitable target for drug intervention. The most potent known inhibitors are analogs of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en), particularly the 4-guanidino derivative (4-guanidino-Neu5Ac2en). We utilized the benzene ring of 4-(N-acetylamino)benzoic acids as a cyclic template to substitute for the dihydropyran ring of Neu5Ac2en. In this study several 3-(N-acylamino) derivatives were prepared as potential replacements for the glycerol side chain of Neu5Ac2en, and some were found to interact with the same binding subsite of sialidase. Of greater significance was the observation that the 3-guanidinobenzoic acid derivative (equivalent to the 4-guanidino grouping of 4-guanidino-Neu5Ac2en), the most potent benzoic acid inhibitor of influenza sialidase thus far identified (IC50 = 10 microM), occupied the glycerol-binding subsite on sialidase as opposed to the guanidino-binding subsite. This benzoic acid derivative thus provides a new compound that interacts in a novel manner with the catalytic site of influenza sialidase.
流感病毒唾液酸酶是一种表面酶，对病毒感染至关重要。催化位点在所有已知的流感病毒变体中高度保守，这表明该蛋白是药物干预的合适靶点。已知最有效的抑制剂是2-脱氧-2,3-二脱氢-N-乙酰神经氨酸（Neu5Ac2en）的类似物，特别是4-胍基衍生物（4-胍基-Neu5Ac2en）。我们利用4-（N-乙酰氨基）苯甲酸的苯环作为环状模板来替代Neu5Ac2en的二氢吡喃环。在本研究中，制备了几种3-（N-酰基氨基）衍生物作为Neu5Ac2en甘油侧链的潜在替代物，并且发现其中一些与唾液酸酶的相同结合亚位点相互作用。更重要的是观察到，3-胍基苯甲酸衍生物（相当于4-胍基-Neu5Ac2en的4-胍基基团），是迄今为止鉴定出的最有效的流感唾液酸酶苯甲酸抑制剂（IC50 = 10 microM），它占据了唾液酸酶上的甘油结合亚位点，而不是胍基结合亚位点。因此，这种苯甲酸衍生物提供了一种以新颖方式与流感唾液酸酶催化位点相互作用的新化合物。
