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

基本信息

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
项目类别：
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

项目摘要

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，可有效抑制流感 M2 质子通道最常见的 S31N 耐药突变体，该突变体是已上市抗流感药物金刚烷胺和金刚烷胺的靶标。我们在此建议利用我们在该领域广泛的结构生物学工作来设计新的相关类似物，以提高最常见突变体和野生型 M2 的效力，并了解和改善药物样特性最终发现针对季节性流感感染的新疗法除了每年爆发的流行病外，流感病毒由于具有引起大流行的能力而成为更具威胁性的病原体，正如 2009 年 H1N1 病毒的出现和全球传播所发生的那样。对新出现的流感病毒株完全有效；因此，有效的抗病毒治疗不是我们抗击流感的辅助药物，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[Symmetrel（金刚烷胺）和氟马定（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）]虽然这些药物可以有效减轻流感症状，但耐药性的增加严重限制了它们的有效性。药物类别与自然发生点相关 M2 通道孔中的突变由穿过病毒外层的单螺旋链组成，四个 M2 蛋白一起形成功能性质子通道。单个突变的效果会放大四倍，因为它存在于所有孔中。 S31N 突变体是最常见和最显着的金刚烷胺抗性突变体，它存在于几乎所有当前流行的流感病毒株以及 2009 年禽流感病毒株中。因此，迫切需要开发针对所有临床相关 M2 突变体，特别是最流行的 S31N 突变体的第二代新型 M2 抑制剂。针对 S31N 以及其他具有临床意义的 M2 变体（例如 V27A）的化合物我们的首要目标是使用现有系列的 M2-S31N 抑制剂来优化体外亲和力和药物样特性。基于我们对孔的 3-D 结构的理解，我们具有独特的优势来做到这一点，第二个目标是优化不同系列顶级代表性成员的体外 ADME 特性，用于体内探针。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功效和毒性测试来推进第一阶段确定的最有前途的先导候选药物，最终目标是确定。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。