Development of group 2 influenza A virus entry inhibitors

甲型流感病毒属于正粘病毒科负感病毒家族， 节段性RNA基因组，可导致高发病率的季节性或大流行性流感 以及显著的死亡率。接种疫苗是最普遍的预防手段 控制流感感染。然而，一种有效的疫苗通常需要至少6 需要几个月的时间才能形成循环菌株。此外，疫苗接种有限。 对免疫功能低下患者的治疗效果，其有效性也 在大流行期间是有限的。目前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)不再被推荐，因为所有正在传播的流感 菌株对它们具有抗药性。然而，耐NAI菌株的迅速出现 甲型流感病毒的研究强烈表明，仅有NAI可能不足以作为 有效的抗流感治疗手段，从而针对 迫切需要其他病毒/宿主因素。此应用程序定义了要开发的计划 有效的小分子抑制剂，可阻止甲型流感病毒进入。我们有 已确定的化合物可抑制传染性甲型流感病毒进入(IC50值为≤1 µM)。这些HIT化合物表现出对H3N2和H7N1进入的选择性。整体而言 这一阶段应用的目标是开发这些潜在的抗流感药物 治疗学。本申请将侧重于以下三个具体目标：(1) 基于以下内容合成结构多样的抗流感CBS1193热门系列类似物 结构-活性关系(SARS)，以提高效力和选择性。(2) 在感染试验中验证候选的铅抑制物，并调查 抑制剂的作用机制(MOA)。(3)用体外ADME筛选流感抑制剂 适合静脉注射的特性。和口服剂量。

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.