Boehringer-Ingelheim (Canada) Ltd., Laval, Québec, Canada.
Antimicrob Agents Chemother. 2013 Jul;57(7):3358-68. doi: 10.1128/AAC.00303-13. Epub 2013 May 6.
Human rhinovirus (HRV) is the predominant cause of the common cold, but more importantly, infection may have serious repercussions in asthmatics and chronic obstructive pulmonary disorder (COPD) patients. A cell-based antiviral screen against HRV was performed with a subset of our proprietary compound collection, and an aminothiazole series with pan-HRV species and enteroviral activity was identified. The series was found to act at the level of replication in the HRV infectious cycle. In vitro selection and sequencing of aminothiazole series-resistant HRV variants revealed a single-nucleotide mutation leading to the amino acid change I42V in the essential HRV 3A protein. This same mutation has been previously implicated in resistance to enviroxime, a former clinical-stage antipicornavirus agent. Enviroxime-like compounds have recently been shown to target the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ). A good correlation between PI4KIIIβ activity and HRV antiviral potency was found when analyzing the data over 80 compounds of the aminothiazole series, covering a 750-fold potency range. The mechanism of action through PI4KIIIβ inhibition was further demonstrated by small interfering RNA (siRNA) knockdown of PI4KB, which reduced HRV replication and also increased the potency of the PI4KIIIβ inhibitors. Inhibitors from two different structural classes with promising pharmacokinetic profiles and with very good selectivity for PI4KIIIβ were used to dissociate compound-related toxicity from target-related toxicity. Mortality was seen in all dosing groups of mice treated with either compound, therefore suggesting that short-term inhibition of PI4KIIIβ is deleterious.
人鼻病毒（HRV）是普通感冒的主要病因，但更重要的是，感染可能对哮喘和慢性阻塞性肺疾病（COPD）患者产生严重影响。我们使用一部分专有的化合物库对 HRV 进行了基于细胞的抗病毒筛选，发现了具有泛 HRV 种属和肠道病毒活性的氨基噻唑系列。该系列被发现作用于 HRV 感染周期的复制水平。对氨基噻唑系列耐药的 HRV 变异体进行体外选择和测序，揭示了一个单核苷酸突变，导致必需的 HRV 3A 蛋白中的氨基酸变化 I42V。这种突变之前曾与 enviroxime 有关，后者是一种以前处于临床阶段的抗小核糖核酸病毒药物。最近已经表明，enviroxime 样化合物靶向脂质激酶磷脂酰肌醇 4-激酶 IIIβ（PI4KIIIβ）。在分析涵盖 750 倍效力范围的氨基噻唑系列中的 80 多种化合物的数据时，发现 PI4KIIIβ 活性与 HRV 抗病毒效力之间存在良好的相关性。通过针对 PI4KB 的小干扰 RNA（siRNA）敲低进一步证明了通过 PI4KIIIβ 抑制的作用机制，这降低了 HRV 的复制，并且还增加了 PI4KIIIβ 抑制剂的效力。使用两种具有有前途的药代动力学特征和对 PI4KIIIβ 具有很好选择性的不同结构类别抑制剂将化合物相关毒性与靶标相关毒性分离。用两种化合物处理的所有剂量组的小鼠都出现了死亡，因此表明短期抑制 PI4KIIIβ 是有害的。
