Human rhinoviruses (hRVs) cause upper and lower respiratory tract infections and exacerbate asthma and chronic obstructive pulmonary disease. hRVs comprise more than 160 strains with considerable genetic variation. Their high diversity and strain-specific interactions with antisera hinder the development of anti-hRV therapeutic agents. Phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) is a key enzyme in the phosphoinositide signalling pathway that is crucial for the replication and survival of various viruses. We identified novel PI4KIIIβ inhibitors, N-(4-methyl-5-arylthiazol)-2-amide derivatives, by generating a hit compound, 1a, from the high-throughput screening of a chemical library, followed by the optimization study of 1a. Inhibitor 7e exhibited the highest activity (EC₅₀ = 0.008, 0.0068, and 0.0076 μM for hRV-B14, hRV-A16, and hRV-A21, respectively) and high toxicity (CC₅₀ = 6.1 μM). Inhibitor 7f showed good activity and low toxicity and provided the highest selectivity index (SI ≥ 4638, >3116, and >2793 for hRV-B14, hRV-A16, and hRV-A21, respectively). Furthermore, 7f showed broad-spectrum activities against various hRVs, coxsackieviruses, and other enteroviruses, such as EV-A71 and EV-D68. The binding mode of the inhibitors was investigated using 7f, and the experimental results of plaque reduction, replicon and cytotoxicity, and time-of-drug-addition assays suggested that 7f acts as a PI4KIIIβ inhibitor. The kinase inhibition activity of this series of compounds against PI4KIIIα and PI4KIIIβ was assessed, and 7f demonstrated kinase inhibition activity with an IC₅₀ value of 0.016 μM for PI4KIIIβ, but not for PI4KIIIα (>10 μM). Therefore, 7f represents a highly potent and selective PI4KIIIβ inhibitor for the further development of antiviral therapy against hRVs or other enteroviruses.

中文翻译：

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作为广谱抗鼻病毒药物的高效选择性磷脂酰肌醇 4-激酶 IIIβ 抑制剂

人类鼻病毒（hRV）会引起上呼吸道和下呼吸道感染，并加剧哮喘和慢性阻塞性肺病。 hRV 包含 160 多个具有相当大遗传变异的菌株。它们的高度多样性以及与抗血清的菌株特异性相互作用阻碍了抗 hRV 治疗剂的开发。磷脂酰肌醇-4-激酶 IIIβ (PI4KIIIβ) 是磷酸肌醇信号通路中的关键酶，对于各种病毒的复制和生存至关重要。我们通过从化学库的高通量筛选中生成命中化合物1a ，然后对1a进行优化研究，鉴定了新型 PI4KIIIβ 抑制剂N -(4-甲基-5-芳基噻唑)-2-酰胺衍生物。抑制剂7e表现出最高的活性（hRV-B14、hRV-A16 和 hRV-A21 的 EC ₅₀分别为 0.008、0.0068 和 0.0076 μM）和高毒性（CC ₅₀ = 6.1 μM）。抑制剂7f表现出良好的活性和低毒性，并提供最高的选择性指数（hRV-B14、hRV-A16和hRV-A21的SI≥4638、>3116和>2793，分别）。此外，7f对各种 hRV、柯萨奇病毒和其他肠道病毒（例如 EV-A71 和 EV-D68）表现出广谱活性。使用7f研究抑制剂的结合模式，噬菌斑减少、复制子和细胞毒性以及药物添加时间测定的实验结果表明7f作为 PI4KIIIβ 抑制剂。评估了该系列化合物对PI4KIIIα和PI4KIIIβ的激酶抑制活性，7f显示了对PI4KIIIβ的激酶抑制活性，IC ₅₀值为0.016 μM，但对PI4KIIIα没有激酶抑制活性（>10 μM）。因此，7f代表了一种高效、选择性的 PI4KIIIβ 抑制剂，可用于进一步开发针对 hRV 或其他肠道病毒的抗病毒治疗。