DEVELOPMENT OF DRUGS THAT TARGET THE M2 PROTON CHANNEL FROM INFLUENZA A VIRUS

 描述(申请人提供)：我们发现了第一个有效抑制流感M2质子通道最流行的S31N耐药突变的小分子探针和候选药物，该突变是上市抗流感药物金刚烷胺和金刚乙胺的靶标。我们建议利用我们在这一领域的广泛结构生物学工作来设计新的、相关的类似物，以提高对最流行的突变株和野生型M2的效力，并了解和改进药物样特性，最终发现治疗季节性流感感染的新方法。除了每年的疫情暴发，流感病毒由于其引发大流行的效力而更具威胁性，正如2009年H1N1病毒的出现和全球传播所发生的那样。现有的预防性疫苗对新出现的流感病毒株并不是完全有效的；因此，有效的抗病毒治疗不是我们抗击流感的一个辅助选择，而是一个必不可少的组成部分。目前有两类药物被批准用作抗病毒药物：M2质子通道抑制剂[Symmetrel(金刚烷胺)和Flumadine(金刚乙胺)]和神经氨酸酶抑制剂[达菲(奥司他韦)和瑞乐沙(扎那米韦)]。虽然这些药物在减轻流感症状方面是有效的，但耐药性的增加严重限制了它们的有效性。对这类药物的耐药性与自然发生点有关 M2通道孔中的突变，由穿过病毒外层的单个螺旋链组成，以及四个M2蛋白结合在一起形成了一个功能强大的质子通道。单一突变的影响被放大四倍，因为它存在于毛孔的所有四个螺旋中。S31N突变是最普遍和最显著的金刚烷胺耐药突变。它存在于几乎所有目前流行的流感毒株以及2009年新一代禽流感大流行H1N1毒株中。因此，迫切需要开发针对所有临床相关的M2突变，特别是最流行的S31N突变的第二代新型M2抑制剂。目前的工作已经确定了几个新的和有效的(体外)化合物系列，以及其他临床上有意义的M2变种，如V27A。我们的第一个目标是利用迭代药物化学优化现有的M2-S31N抑制剂系列的体外亲和力和类药物性质。根据我们对毛孔的三维结构的理解，我们处于独特的位置来做这件事。第二个目标是优化不同系列的顶级代表成员的体外ADME特性，以获得体内探针和类药物的适合性。在第二阶段，我们将通过药代动力学分析、额外的ADME和非靶标安全性研究以及动物疗效和毒性试验，推进在第一阶段确定的最有希望的候选药物，最终目标是确定 一个或多个开发候选对象。该计划的长期目标是完成提交研究新药(IND)申请所需的所有研究。

 DESCRIPTION (provided by applicant): We have the discovered the first small-molecule probes and drug candidates that effectively inhibit the most prevalent S31N drug-resistant mutant of the M2 proton channel of influenza, the target of the marketed anti-flu drugs amantadine and rimantadine. We here propose to exploit our extensive structural biology work in this area to design new, related analogs to increase potency for both the most prevalent mutants and wild-type M2, and to understand and improve drug-like properties to eventually discover new treatments for seasonal influenza infections. Besides the yearly epidemic outbreaks, influenza viruses are even more threatening pathogens due to their potency to cause pandemics, as occurred in 2009 by the emergence and worldwide spread of the H1N1 viruses. Available prophylactic vaccines are not completely effective against emerging flu strains; thus, effective anti-viral therapy is not an adjunct but an essential component of our options in the fight against influenza. Two classes of drugs are currently approved as antiviral agents: the M2 proton channel inhibitors [Symmetrel (amantadine) and Flumadine (rimantadine)] and the neuraminidase inhibitors [Tamiflu (oseltamivir) and Relenza (zanamivir)]. While these drugs are effective in reducing symptomatology from influenza, increasing resistance has severely limited their effectiveness. Resistance to this class of drugs is associated with naturally occurring point mutations in the M2 channel pore, comprised of a single helical strand through the virus outer coat, and four of the M2 proteins taken together form a functional proton channel. The effect of a single mutation is amplified four fold, because it is present in all four of the helices that for the pore. The S31N mutant is the most prevalent and significant amantadine-resistant mutation. It is present in almost all of the currently circulating influenza strains as well as in the avian nd 2009 pandemic H1N1 strains. As a result, there is an urgent need to develop second generation novel M2 inhibitors targeting all clinically relevant mutants of M2, and particularly the most prevalent S31N mutant. Current efforts have already identified several series of novel and potent (in vitro) compounds against S31N as well as other clinically significant M2 variants such as V27A. Our first aim is to optimize the in vitro affinities and drug-like properties of the existng series of M2-S31N inhibitors using iterative medicinal chemistry. We are uniquely situated to do this based upon our understanding as to the 3-D structure of the pore. The second aim is to optimize the in vitro ADME properties of top representative members of different series, for in vivo probe- and drug-like suitability. In Phase II we will advance the most promising lead candidates identified in Phase I through pharmacokinetic profiling, additional ADME and off-target safety studies, and animal efficacy and toxicity tests with the ultimate goal of identifying one or more development candidates. The long term goal of the program is to complete all studies necessary for filing an Investigational New Drug (IND) application.