Novel α- and β-amino acid inhibitors of influenza virus neuraminidase
Novel α- and β-amino acid inhibitors of influenza virus neuraminidase
复制标题
DOI：
10.1128/aac.45.9.2563-2570.2001
复制
发表时间：
2001-09-01
影响因子：
4.9
通讯作者：
Norbeck, DW
中科院分区：
文献类型：
--
作者：
Kati, WM;Montgomery, D;Norbeck, DW
为了发现流感病毒神经氨酸酶的新的非碳水化合物抑制剂，我们假设在适当位置含有带正电荷的氨基的化合物可能与Asp 152或Tyr 406侧链紧密结合。对300个α和β氨基酸的测试导致发现了两种新的神经氨酸酶抑制剂，苯甘氨酸和吡咯烷，与流感病毒A/N2/Tokyo/3/67神经氨酸酶相比，它们的K-I值在50微米范围内，但对流感病毒B/孟菲斯/3/89神经氨酸酶的活性较弱。对吡咯烷系列进行了有限的优化，得到了一种化合物，在使用A/N2NicVictoria/3/75病毒进行的抗流感细胞培养试验中，该化合物的效力约为2-脱氧-2，3-脱氢-N-乙酰神经氨酸的24倍。对A/N9神经氨酸酶抑制剂复合体的X-射线结构研究表明，这两类抑制剂都能诱导Glu 278侧链发生微小的构象变化，但这些化合物没有表现出时间依赖性的抑制作用。结晶学还证实，苯甘氨酸的α-氨基如预期的那样与天冬氨酸152羧酸盐形成氢键。同样，吡咯烷的β-氨基与酪氨酸406羟基形成相互作用，并代表已知的第一个与这一绝对保守的残基相互作用的化合物。α-或β-氨基被羟基取代的苯甘氨酸和吡咯烷类似物分别是365和2600倍弱的抑制剂。这些结果强调了氨基与Asp 152和Tyr 406侧链相互作用的重要性，并对抗流感药物设计具有指导意义。
In an effort to discover novel, noncarbohydrate inhibitors of influenza virus neuraminidase we hypothesized that compounds which contain positively charged amino groups in an appropriate position to interact with the Asp 152 or Tyr 406 side chains might be bound tightly by the enzyme. Testing of 300 alpha- and beta -amino acids led to the discovery of two novel neuraminidase inhibitors, a phenylglycine and a pyrrolidine, which exhibited K-i values in the 50 muM range versus influenza virus A/N2/Tokyo/3/67 neuraminidase but which exhibited weaker activity against influenza virus B/Memphis/3/89 neuraminidase. Limited optimization of the pyrrolidine series resulted in a compound which was about 24-fold more potent than 2-deoxy-2,3-dehydro-N-acetylneuraminic acid in an anti-influenza cell culture assay using A/N2Nictoria/3/75 virus. X-ray structural studies of A/N9 neuraminidase-inhibitor complexes revealed that both classes of inhibitors induced the Glu 278 side chain to undergo a small conformational change, but these compounds did not show time-dependent inhibition. Crystallography also established that the alpha -amino group of the phenylglycine formed hydrogen bonds to the Asp 152 carboxylate as expected. Likewise, the beta -amino group of the pyrrolidine forms an interaction with the Tyr 406 hydroxyl group and represents the first compound known to make an interaction with this absolutely conserved residue. Phenylglycine and pyrrolidine analogs in which the alpha- or beta -amino groups were replaced with hydroxyl groups were 365- and 2,600-fold weaker inhibitors, respectively. These results underscore the importance of the amino group interactions with the Asp 152 and Tyr 406 side chains and have implications for anti-influenza drug design.