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（由适用提供）：我们发现了第一个小分子问题和候选药物，这些问题有效地抑制了影响力的M2质子通道的最普遍的S31N药物耐药突变体，这是销售的抗FLU药物amantadine和Rimantadine的靶标。我们在这里建议探索我们在该领域的广泛结构生物学工作，以设计新的，相关的类似物，以提高最普遍的突变体和野生型M2的效力，并了解和改善类似药物的特性，以最终发现季节性影响感染的新治疗方法。除了每年的流行病暴发外，由于其引起大流行病的效力，影响病毒更具威胁性的病原体，如2009年，H1N1病毒的出现和全球传播所发生的那样。可用的预防性疫苗并不完全有效，以防止新兴的流感菌株；因此，有效的抗病毒疗法不是我们在与影响力斗争中选择的辅助疗法，而是我们选择的重要组成部分。目前两类药物被批准为抗病毒剂：M2质子通道抑制剂[symmetrel（amantadine）和氟马丁（Rimantadine）]和神经粒酶抑制剂[tamiflu（oseltallivir）和relenza（Zanamivir）]。尽管这些药物可有效减少流感症状学，但增加的耐药性严重限制了它们的有效性。对这类药物的抵抗力与自然发生的点有关 M2通道孔中的突变，由单个螺旋链穿过病毒外层，而四种M2蛋白在一起形成功能性质子通道。单个突变的效果将其扩展到四倍，因为它呈现在孔的所有四个螺旋中。 S31N突变体是最普遍，最明显的抗肿瘤的突变。它几乎存在于目前所有循环的影响菌株以及鸟类ND 2009年大流行H1N1菌株中。结果，迫切需要开发针对M2的所有临床相关突变体，尤其是最普遍的S31N突变体的第二代小说M2抑制剂。当前的努力已经确定了针对S31N以及其他临床意义的M2变体（例如V27A）的几种新型和潜力（体外）化合物。我们的第一个目的是使用迭代医学化学优化现有的M2-S31N抑制剂的体外亲和力和类似药物样性能。根据我们对孔的3-D结构的理解，我们本地可以做到这一点。第二个目的是优化代表不同系列成员的体外ADME特性，用于体内探针和类似药物的适合性。在第二阶段，我们将通过药代动力学分析，额外的ADME和非目标安全研究以及动物效率和毒性测试来推进第一阶段中最有希望的主要候选者 一个或多个开发候选人。该计划的长期目标是完成提交研究新药（IND）应用所需的所有研究。