Shen Zuyuan, Lou Kaiyan, Wang Wei
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, and State Key Laboratory of Bioengineering Reactor, East China University of Science and Technology, Shanghai 200237, China.
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, and State Key Laboratory of Bioengineering Reactor, East China University of Science and Technology, Shanghai 200237, China ; Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131-0001, USA.
Acta Pharm Sin B. 2015 Sep;5(5):419-30. doi: 10.1016/j.apsb.2015.07.006. Epub 2015 Sep 6.
Influenza A virus is the major cause of seasonal or pandemic flu worldwide. Two main treatment strategies-vaccination and small molecule anti-influenza drugs are currently available. As an effective vaccine usually takes at least 6 months to develop, anti-influenza small molecule drugs are more effective for the first line of protection against the virus during an epidemic outbreak, especially in the early stage. Two major classes of anti-influenza drugs currently available are admantane-based M2 protein blockers (amantadine and rimantadine) and neuraminidase (NA) inhibitors (oseltamivir, zanamivir, and peramivir). However, the continuous evolvement of influenza A virus and the rapid emergence of resistance to current drugs, particularly to amantadine, rimantadine, and oseltamivir, have raised an urgent need for developing new anti-influenza drugs against resistant forms of influenza A virus. In this review, we first give a brief introduction of the molecular mechanisms behind resistance, and then discuss new strategies in small-molecule drug development to overcome influenza A virus resistance targeting mutant M2 proteins and neuraminidases, and other viral proteins not associated with current drugs.
甲型流感病毒是全球季节性流感或大流行性流感的主要病因。目前有两种主要治疗策略——疫苗接种和小分子抗流感药物。由于一种有效的疫苗通常至少需要6个月才能研发出来，因此抗流感小分子药物在疫情爆发期间，尤其是在早期阶段，对于抵御病毒的一线防护更为有效。目前可用的两大类抗流感药物是基于金刚烷的M2蛋白阻滞剂（金刚烷胺和金刚乙胺）以及神经氨酸酶（NA）抑制剂（奥司他韦、扎那米韦和帕拉米韦）。然而，甲型流感病毒的持续演变以及对当前药物，尤其是对金刚烷胺、金刚乙胺和奥司他韦耐药性的迅速出现，迫切需要研发针对甲型流感病毒耐药形式的新型抗流感药物。在本综述中，我们首先简要介绍耐药背后的分子机制，然后讨论小分子药物研发中的新策略，以克服针对突变M2蛋白和神经氨酸酶以及其他与当前药物无关的病毒蛋白的甲型流感病毒耐药性。
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