Limited inhibitory effects of oseltamivir and zanamivir on human sialidases
Limited inhibitory effects of oseltamivir and zanamivir on human sialidases
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DOI：
10.1128/aac.00344-08
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发表时间：
2008-10-01
影响因子：
4.9
通讯作者：
Miyagi, Taeko
中科院分区：
文献类型：
--
作者：
Hata, Keiko;Koseki, Koichi;Miyagi, Taeko
奥司他韦（达菲）和扎那米韦（瑞乐沙），两种广泛使用的临床有效的抗流感药物，是病毒唾液酸酶（也称为神经氨酸酶）抑制剂，可防止子代病毒粒子的释放，从而限制感染的传播。最近报告了使用奥司他韦导致的死亡和神经精神事件，尤其是在日本的儿科病例中，这表明这些药物除了对病毒唾液酸酶具有抑制作用外，还可能抑制参与唾液酸代谢的内源性酶，包括唾液酸酶、唾液酸转移酶和CMP合酶。这种可能的抑制作用可以解释奥司他韦的一些罕见副作用。然而，几乎没有直接证据表明动物唾液酸酶对这些药物的敏感性。在这里，我们研究了这些抑制剂是否可能确实影响人类唾液酸酶的活性，这些唾液酸酶在一级结构和酶性质上不同，但具有与病毒酶相似的三级结构。使用与迄今为止鉴定的四种人唾液酸酶相对应的重组酶，我们发现奥司他韦羧酸盐几乎不影响任何唾液酸酶的活性，即使在1 mM时，而扎那米韦在微摩尔范围内显著抑制人唾液酸酶NEU 3和NEU 2（Ki，分别为3.7 +/-0.48和12.9 +/-0.07 μ M），与这些药物阻断病毒唾液酸酶活性的低纳摩尔浓度形成对比。
Oseltamivir (Tamiflu) and zanamivir (Relenza), two extensively used clinically effective anti-influenza drugs, are viral sialidase (also known as neuraminidase) inhibitors that prevent the release of progeny virions and thereby limit the spread of infection. Recently mortalities and neuropsychiatric events have been reported with the use of oseltamivir, especially in pediatric cases in Japan, suggesting that these drugs might also inhibit endogenous enzymes involved in sialic acid metabolism, including sialidase, sialyltransferase, and CMP-synthase, in addition to their inhibitory effects on the viral sialidase. The possible inhibition could account for some of the rare side effects of oseltamivir. However, there has been little direct evidence in regard to the sensitivities of animal sialidases to these drugs. Here, we examined whether these inhibitors might indeed affect the activities of human sialidases, which differ in primary structures and enzyme properties but possess tertiary structures similar to those of the viral enzymes. Using recombinant enzymes corresponding to the four human sialidases identified so far, we found that oseltamivir carboxylate scarcely affected the activities of any of the sialidases, even at 1 mM, while zanamivir significantly inhibited the human sialidases NEU3 and NEU2 in the micromolar range (K-i, 3.7 +/- 0.48 and 12.9 +/- 0.07 mu M, respectively), providing a contrast to the low nanomolar concentrations at which these drugs block the activity of the viral sialidases.