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

开发针对甲型流感病毒 M2 质子通道的药物

• 批准号: 9247305
• 负责人: Allen Bernard Reitz
• 金额: $ 4万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-11 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247305
• 关键词: 3-Dimensional; ADME Study; Adamantane; Address; Affinity; Amantadine; Amantadine resistance; Antiviral Agents; Area; Arizona; Binding Proteins; Biological Assay; Birds; California; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; Collaborations; Communicable Diseases; Development; Disease Outbreaks; Doctor of Philosophy; Drug Design; Drug Kinetics; Drug Targeting; Drug resistance; Effectiveness; Electrophysiology (science); Epidemic; Flumadine; Foxes; Generations; Goals; Health; Hospitalization; In Vitro; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Investigational New Drug Application; Lead; Life; M2 protein; Marketing; Metabolism; Methods; Mutation; Neuraminidase inhibitor; Oseltamivir; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasma Proteins; Point Mutation; Positioning Attribute; Property; Protons; Recommendation; Research Personnel; Resistance; Rimantadine; San Francisco; Series; Structure; Structure-Activity Relationship; Toxic effect; Toxicity Tests; Universities; Vaccines; Variant; Viral; Viral Drug Resistance; Virus; Work; analog; animal efficacy; anti-influenza; anti-influenza drug; base; chemical property; chemical synthesis; clinically relevant; clinically significant; cytotoxicity; design; disorder prevention; drug candidate; drug discovery; efficacy evaluation; efficacy testing; experience; fight against; flu; improved; in vitro testing; in vivo; influenza epidemic; influenza virus strain; influenzavirus; inhibitor/antagonist; member; metabolic abnormality assessment; mutant; next generation; novel; pandemic disease; pathogen; programs; prophylactic; safety study; seasonal influenza; small molecule; structural biology; symptomatology; zanamivir

 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.

 描述（由申请人提供）：我们发现了第一个小分子探针和候选药物，其有效抑制流感M2质子通道的最普遍的S31 N耐药突变体，该突变体是市售抗流感药物金刚烷胺和金刚乙胺的靶点。我们在这里建议利用我们在这一领域广泛的结构生物学工作来设计新的相关类似物，以增加最流行的突变体和野生型M2的效力，并了解和改善药物样特性，最终发现季节性流感感染的新疗法。除了每年的流行病爆发之外，流感病毒是更具威胁性的病原体，因为它们具有引起大流行的潜力，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完全有效;因此，有效的抗病毒治疗不是我们对抗流感的选择的辅助手段，而是重要组成部分。目前有两类药物被批准作为抗病毒药物：M2质子通道抑制剂[金刚烷胺和金刚乙胺]和神经氨酸酶抑制剂[达菲（奥司他韦）和瑞乐沙（扎那米韦）]。虽然这些药物在减少流感的副作用方面是有效的，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的点 M2通道孔中的突变，由穿过病毒外壳的单个螺旋链组成，并且四个M2蛋白一起形成功能性质子通道。单个突变的影响被放大四倍，因为它存在于孔的所有四个螺旋中。S31 N突变体是最普遍和最重要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禽流感和2009年大流行性H1N1毒株中。因此，迫切需要开发靶向M2的所有临床相关突变体，特别是最普遍的S31 N突变体的第二代新型M2抑制剂。目前的努力已经确定了几个系列的新的和有效的（体外）化合物对S31 N以及其他临床上重要的M2变异体，如V27 A。我们的第一个目标是使用迭代药物化学优化现有系列M2-S31 N抑制剂的体外亲和力和药物样性质。基于我们对孔隙三维结构的理解，我们处于独特的位置。第二个目标是优化不同系列的顶级代表性成员的体外ADME特性，以实现体内探针和药物样适用性。在第二阶段，我们将通过药代动力学分析、额外的ADME和脱靶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先导候选药物，最终目标是确定 一个或多个候选人。该计划的长期目标是完成提交研究性新药（IND）申请所需的所有研究。