Development of group 2 influenza A virus entry inhibitors

2 组甲型流感病毒侵入抑制剂的开发

• 批准号: 9903216
• 负责人: Lijun Rong
• 金额: $ 30万
• 依托单位: CHICAGO BIOSOLUTIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903216
• 关键词: Affect; Affinity; Amantadine; Animal Model; Animal Testing; Anti-influenza Agent; Antiviral Agents; Biological Assay; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Communicable Diseases; Development; Dose; Drug Kinetics; Effectiveness; Epidemic; Exhibits; Family; Genome; Goals; Grant; H7 hemagglutinin; Health; Hemagglutinin; Immunocompromised Host; In Vitro; Influenza; Influenza A virus; Influenza Therapeutic; Integration Host Factors; Lead; Libraries; Life; Liver Microsomes; Mediating; Morbidity - disease rate; Mutation; National Institute of Allergy and Infectious Disease; Oral; Orthomyxoviridae; Oseltamivir; Permeability; Pharmaceutical Preparations; Phase; Population; Property; Protein Isoforms; Proteins; Pyrimidine; Pyrimidines; RNA; RNA Viruses; Research; Rimantadine; Series; Small Business Technology Transfer Research; Structure; Structure-Activity Relationship; Therapeutic; Toxic effect; Vaccination; Vaccines; Viral; Virulent; Virus; Virus Diseases; Virus Inhibitors; analog; anti-influenza; base; clinical candidate; cytotoxicity; design; drug development; flu; improved; indexing; influenza M2; influenza virus vaccine; influenzavirus; inhibitor/antagonist; ion channel blocker; mortality; mouse model; neutralizing antibody; novel therapeutics; pandemic disease; pandemic influenza; prophylactic; protein H(3); resistant strain; scaffold; seasonal influenza; small molecule; small molecule inhibitor; social; tissue culture

Influenza A viruses belong to the Orthomyxoviridae family with a negative-sense, segmented RNA genome, which can cause seasonal or pandemic flu with high morbidity and significant mortality. Vaccination is the most prevalent prophylactic means for controlling influenza infections. However, an effective vaccine usually takes at least 6 months to develop for the circulating strains. Furthermore, vaccination has limited effectiveness in treatment of immunocompromised patients, and its effectiveness is also limited during a pandemic. The current therapeutic options for flu infections are all based on the NA inhibitors (NAIs), while the influenza M2 ion channel blockers (amantadine and rimantadine) are not recommended anymore since all the circulating influenza strains are resistant to them. However, the rapid emergence of the NAI-resistant strains of influenza A viruses strongly suggests that NAIs alone may not be sufficient as an effective means of the anti-flu therapies, and thus new treatment options targeting the other viral/host factors are urgently needed. This application defines a plan to develop potent, small molecule inhibitors, which block entry of influenza A viruses. We have identified compounds that inhibit entry of infectious influenza A viruses (IC50 values ≤1 µM). These hit compounds exhibit selectivity for H3N2 and H7N1 entry. The overall objective of this Phase I application is to develop these inhibitors as potential anti-flu therapeutics. This application will focus on the following three specific aims: (1) Synthesize structurally diverse analogs of the anti-flu CBS1193 hit series based on structure-activity relationships (SARs) to improve potency and selectivity. (2) Validateothe lead inhibitor candidates in the infectious assay and investigate the mechanism of action (MOA) of the inhibitors. (3) Select flu inhibitors with in vitro ADME properties suitable for i.v. and oral dosing.

甲型流感病毒属于正粘病毒科，具有负义， 分段RNA基因组，可引起高发病率的季节性或大流行性流感 和显着的死亡率。疫苗接种是最普遍的预防手段 控制流感感染。然而，有效的疫苗通常至少需要 6 流行菌株的发育需要几个月的时间。此外，疫苗接种也受到限制 治疗免疫功能低下患者的有效性，其有效性也 疫情期间受到限制。目前针对流感感染的治疗选择都是基于 NA抑制剂（NAIs），而流感M2离子通道阻滞剂（金刚烷胺） 和金刚乙胺）不再推荐，因为所有正在流行的流感 菌株对它们有抵抗力。然而，NAI 抗性菌株的迅速出现 甲型流感病毒的研究强烈表明，单独的 NAI 可能不足以作为一种治疗方法。 抗流感治疗的有效手段，因此针对流感的新治疗方案 迫切需要其他病毒/宿主因素。该应用程序定义了一个开发计划 有效的小分子抑制剂，可阻止甲型流感病毒的进入。我们有 确定了抑制传染性甲型流感病毒进入的化合物（IC50值≤1 微米）。这些命中化合物对 H3N2 和 H7N1 进入具有选择性。整体 第一阶段应用的目标是开发这些抑制剂作为潜在的抗流感药物 疗法。该应用程序将重点关注以下三个具体目标：（1） 合成抗流感 CBS1193 热门系列的结构多样的类似物 结构-活性关系（SAR）以提高效力和选择性。 (2) 在感染性测定中验证先导抑制剂候选物并研究 抑制剂的作用机制（MOA）。 (3) 用体外 ADME 选择流感抑制剂 适合静脉注射的特性和口服给药。