抗奥塞塔米维尔抗性流感病毒神经胺基酶突变体的晶体结构
Patrick J Collins1, Lesley F Haire, Yi Pu Lin
1MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Nature
|May 16, 2008
概括
疫情流感的准备需要有效的抗病毒药物. H5N1神经aminidase突变体对oseltamivir表现出耐药性,但对zanamivir仍然敏感,这表明需要多样化的药物库存.
科学领域:
- 病毒学 病毒学
- 生物化学 生物化学
- 药物发现 药物发现 药物发现
背景情况:
- 流行性流感对公众健康构成重大威胁,需要采取强有力的控制措施.
- 针对病毒神经氨基酶的抗病毒药物对于控制流感疫情至关重要.
- 目前的流行病计划在很大程度上依赖于储存的神经氨基酶抑制剂,如oseltamivir和zanamivir.
研究的目的:
- 为了研究H5N1流感神经氨基酶突变体中药物耐药性的分子基础.
- 了解对奥塞塔米维尔和扎纳米维尔耐药突变体的不同敏感性.
主要方法:
- 酶分析测定奥塞尔塔米维尔和扎纳米维尔对突变神经aminidases的抑制活性.
- 进行X射线晶体学以确定H5N1神经氨基酶突变的结构.
- 对酶活性部位影响药物结合的结构变化的分析.
主要成果:
- 确定了H5N1神经氨基酶突变,使其对奥塞塔米维尔产生抗药性.
- 结构分析揭示了活性部位的改变的疏水口袋,这对oseltamivir结合至关重要.
- 这些对奥塞塔米维尔耐药的突变仍然容易受到扎纳米维尔的抑制.
结论:
- 这项研究阐明了H5N1流感中奥塞尔塔米维尔耐药性背后的结构机制.
- 这些发现突显了赞纳米维尔作为对抗抗塞尔塔米维尔耐药菌株的替代抗病毒药物的重要性.
- 建议增加各种抗病毒剂的流行病库存,包括扎纳米维尔,以应对新出现的耐药性.
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