Identification of Novel Broad Spectrum Influenza Virus Inhibitors

新型广谱流感病毒抑制剂的鉴定

• 批准号: 8394133
• 负责人: Arnab Basu
• 金额: $ 100万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394133
• 关键词: Acute; Affinity; Alabama; Animal Model; Antiviral Agents; Avian Influenza; Binding; Biological Assay; Biological Availability; Cell membrane; Chemicals; Chicago; Crystallization; Development; Dose; Drug Design; Drug Kinetics; Ensure; Epidemic; Ethers; Evaluation; Exhibits; Failure; Future; Goals; Hemagglutinin; Illinois; In Vitro; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Influenza Hemagglutinin; Influenza Therapeutic; Inhibitory Concentration 50; Institutes; Institution; Lead; Libraries; Liver Microsomes; Lung diseases; Mediating; Membrane Fusion; Modeling; Mus; Neuraminidase inhibitor; Oral; Oseltamivir; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phenols; Process; Property; Protein Isoforms; Recurrence; Research; Research Institute; Research Proposals; Resistance; Safety; Series; Sialic Acids; Solubility; Structure; Structure-Activity Relationship; Sulfonamides; Therapeutic; Toxic effect; Toxicology; Utah; Vaccines; Vesicular stomatitis Indiana virus; Viral; Virus; Virus Diseases; Virus Inhibitors; analog; anti-influenza; aqueous; base; compound 30; cytotoxicity; design; experience; flu activity; hemagglutinin I; high throughput screening; improved; in vitro activity; in vivo; indexing; influenza virus strain; influenzavirus; inhibitor/antagonist; mouse model; novel; pandemic disease; pandemic influenza; phase 3 study; pre-clinical; process optimization; prophylactic; receptor; research and development; resistant strain; response; scaffold; small molecule

DESCRIPTION (provided by applicant): Our goal is to develop small molecule inhibitors that target influenza entry. In Phase I, we identified several compounds that selectively inhibit the hemagglutinin (HA) mediated virus entry process. Three HA specific entry inhibitors (MBX494, MBX994, and MBX726) were selected for further research and development based on their antiviral potency, selectivity and chemical tractability. These influenza inhibitors display high potency (IC50 = 0.3-11 ¿M) and favorable selectivity index values (SI>20-200) against a wide spectrum of influenza virus strains, including the high pathogenic avian influenza (HPAI) A/H5N1, 2009 pandemic influenza A/H1N1 and an oseltamivir resistant A/H1N1 strain. The inhibitors also displayed synergy with the neuraminidase inhibitor, oseltamivir. MBX494, MBX994, and MBX726 act in a group-specific manner to inhibit the H1 and H5 subtypes of group 1 HA but not the H3 or H7 subtypes of group 2 HA. Preliminary mechanism of action (MOA) studies suggest that the compounds act early during infection and inhibit the HA-mediated virus-cell membrane fusion process. Failure of the inhibitors to block influenza viruses with group 2 HA, VSV and LASV, further suggests that they do not act on cellular factors (e.g., endosomal pH, or sialic acid residues or viral/cell membrane). MBX494, MBX994, and MBX726 have aminoalkyl phenol ether, aminoacetamide sulfonamide and simple sulfonamide scaffolds respectively. Preliminary chemical optimization has already generated new active analogs, establishing the suitability of these chemical scaffolds for optimization. In Phase II, we will design, synthesize, and evaluate analogs as HA specific inhibitors. Inhibitor design will be driven by potency, target selectivity, influenza spectrum, synergistic activity with oseltamivir, ad minimal cytotoxicity. The most promising lead inhibitors will be evaluated further for favorable (i in vitro ADME properties, including stability, as well as (ii) in vivo pharmacokinetic (PK) and pharmacodynamic (PD) properties, (iii) toxicity, and (iv) efficacy in animal models to select final pre-clinical candidates. We have five specific aims. In Aim 1, we will design and synthesize analogs of the hit series to establish the SAR and improve potency. We will also use structure based drug design (SBDD) to increase the anti-influenza potency (IC50 <0.1 ¿M) and minimize cytotoxicity (CC50 >100 ¿M). In Aim 2, we will evaluate the analogs for potency and cytotoxicity in vitro to generate 10-20 prioritized leads. In Aim 3, we will further prioritize inhibitors by evaluating in vitro "drug-like" ADME properties. In Aim 4, we will analyze the MOA of anti-influenza activity. In Aim 5, we will validate the prioritized lead inhibitors for efficacy and toxcity in murine models to identify the best preclinical development candidate. Aims 1, 2, 3 and 5 constitute the preclinical candidate optimization process since together they provide the relationships between structure and activity, in vitro ADME and in vivo safety and efficacy in vivo. Understanding the MOA of the newly synthesized analogs will ensure that analogs maintain the desired mechanism and do not acquire additional or different non-specific mechanisms. PUBLIC HEALTH RELEVANCE: Influenza is a highly infectious acute respiratory disease, characterized by recurrent annual epidemics and periodic major worldwide pandemics. Vaccines, currently the primary strategy for protection against influenza virus infection, are only effective if they match the circulating virus type(s) and cannot be developed in advance against new emerging pandemic strain(s). Our goal is to develop an anti-influenza therapeutic that can be used to treat the current neuraminidase inhibitor resistant strains and new pandemic strains.

描述（由申请人提供）：我们的目标是开发针对流感进入的小分子抑制剂。在第一阶段，我们鉴定了几种选择性抑制血凝素（HA）介导的病毒进入过程的化合物。根据其抗病毒效力、选择性和化学可处理性，选择了三种 HA 特异性进入抑制剂（MBX494、MBX994 和 MBX726）进行进一步研究和开发。这些流感抑制剂对多种流感病毒株表现出高效力 (IC50 = 0.3-11 µM) 和良好的选择性指数值 (SI>20-200)，包括高致病性禽流感 (HPAI) A/H5N1、2009 年大流行的 A/H1N1 流感和奥司他韦耐药 A/H1N1 病毒株。这些抑制剂还与神经氨酸酶抑制剂奥司他韦表现出协同作用。 MBX494、MBX994 和 MBX726 以组特异性方式发挥作用，抑制第 1 组 HA 的 H1 和 H5 亚型，但不抑制第 2 组 HA 的 H3 或 H7 亚型。初步作用机制 (MOA) 研究表明，这些化合物在感染早期发挥作用，抑制 HA 介导的病毒-细胞膜融合过程。抑制剂未能用 2 组 HA、VSV 和 LASV 阻断流感病毒，进一步表明它们不作用于细胞因子（例如内体 pH 值或唾液酸残基或病毒/细胞膜）。 MBX494、MBX994和MBX726分别具有氨基烷基苯酚醚、氨基乙酰胺磺酰胺和简单磺酰胺支架。初步的化学优化已经产生了新的活性类似物，确定了这些化学支架的优化适用性。在第二阶段，我们将设计、合成和评估作为HA特异性抑制剂的类似物。抑制剂设计将由效力、靶标选择性、流感谱、与奥司他韦的协同活性以及最小的细胞毒性驱动。最有前途的先导抑制剂将进一步评估其有利的（i 体外 ADME 特性，包括稳定性，以及 (ii) 体内药代动力学 (PK) 和药效学 (PD) 特性，(iii) 毒性，以及 (iv) 在动物模型中的功效，以选择最终的药物 临床前候选人。我们有五个具体目标。在目标 1 中，我们将设计并合成热门系列的类似物，以建立 SAR 并提高效力。我们还将使用基于结构的药物设计 (SBDD) 来提高抗流感效力 (IC50 <0.1 µM) 并最大限度地减少细胞毒性 (CC50 >100 µM)。在目标 2 中，我们将评估类似物的体外效力和细胞毒性，以产生 10-20 个优先线索。在目标 3 中，我们将通过评估体外“类药物”ADME 特性来进一步优先考虑抑制剂。在目标 4 中，我们将分析抗流感活性的 MOA。在目标 5 中，我们将在小鼠模型中验证优先先导抑制剂的功效和毒性，以确定最佳的临床前开发候选药物。目标 1、2、3 和 5 构成了临床前候选物优化过程，因为它们共同提供了结构和活性、体外 ADME 以及体内安全性和有效性之间的关系。了解新合成类似物的 MOA 将确保类似物保持所需的机制，并且不会获得额外的或不同的非特异性机制。 公共卫生相关性：流感是一种传染性极强的急性呼吸道疾病，其特点是每年反复流行和周期性的全球性大流行。疫苗是目前预防流感病毒感染的主要策略，但 如果它们与流行病毒类型相匹配并且无法针对新出现的大流行病毒株提前开发，则有效。我们的目标是开发一种抗流感疗法，可用于治疗当前的神经氨酸酶抑制剂耐药菌株和新的大流行菌株。