Astrahan Peleg, Kass Itamar, Cooper Matthew A, Arkin Isaiah T
Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem, Israel.
Proteins. 2004 May 1;55(2):251-7. doi: 10.1002/prot.20018.
Effective antivirals are few and far between, and as such, the appearance of resistance toward such treatments is an obvious medical concern. In this article, we analyze the mechanism by which influenza attains resistance toward amantadine, a blocker of the viral M2 H(+) channel. Binding analyses of amantadine to M2 peptides from different viral strains showed that the virus has developed two alternate routes to avoid blockage of its channel: (1) a conventional route, in which the channel no longer binds the blocker and, hence, the blocker cannot exert its inhibitory function; and (2) a novel mechanism, in which binding of the blocker is retained, yet the function of the protein is unaffected. Pore diameter profiles revealed the molecular mechanism by which the virus may attain this novel type of resistance: an increase in the size of the channel. Thus, despite the drug binding the channel, it may not be able to block the pore, since the channel diameter has increased. Our findings may have broad ramifications in the design of new antivirals, and of novel blockers against malfunctioning human channels implicated in disease.
有效的抗病毒药物寥寥无几，因此，对这类治疗产生耐药性显然是一个医学问题。在本文中，我们分析了流感病毒对金刚烷胺（一种病毒M2 H(+)通道阻滞剂）产生耐药性的机制。金刚烷胺与不同病毒株的M2肽的结合分析表明，病毒已形成两种避免通道被阻断的替代途径：（1）一种常规途径，通道不再与阻滞剂结合，因此阻滞剂无法发挥其抑制功能；（2）一种新机制，阻滞剂的结合得以保留，但蛋白质的功能不受影响。孔径分布揭示了病毒可能获得这种新型耐药性的分子机制：通道尺寸增大。因此，尽管药物与通道结合，但由于通道直径增大，它可能无法阻断孔道。我们的发现可能对新型抗病毒药物以及针对与疾病相关的功能异常的人类通道的新型阻滞剂的设计产生广泛影响。
