Mechanism-Based Covalent Neuraminidase Inhibitors with Broad-Spectrum Influenza Antiviral Activity
Mechanism-Based Covalent Neuraminidase Inhibitors with Broad-Spectrum Influenza Antiviral Activity
复制标题
DOI：
10.1126/science.1232552
复制
发表时间：
2013-04-05
期刊：
影响因子：
56.9
通讯作者：
Withers, Stephen G.
中科院分区：
文献类型：
--
作者：
Kim, Jin-Hyo;Resende, Ricardo;Withers, Stephen G.
在疫苗制备过程中，流感抗病毒药物在调节疾病严重性和控制大流行方面发挥着重要作用，但对常用神经氨酸酶抑制剂奥司他韦等药物的抗药性的发展可能会限制它们未来的用途。我们在这里报道了一类新的特定的、基于机制的抗流感药物，它们通过在流感神经氨酸酶中形成稳定的共价中间体发挥作用，我们通过结构和机制研究证实了这种作用模式。这些化合物在基于细胞的分析和动物模型中发挥作用，其疗效与神经氨酸酶抑制剂扎那米韦相当，并在体外对耐药菌株具有广谱活性。它们的结构与天然底物的相似之处以及它们基于机制的设计使这些抗病毒候选药物具有吸引力。
Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly used neuraminidase inhibitor oseltamivir may limit their future utility. We report here on a new class of specific, mechanism-based anti-influenza drugs that function through the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and we confirm this mode of action with structural and mechanistic studies. These compounds function in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad-spectrum activity against drug-resistant strains in vitro. The similarity of their structure to that of the natural substrate and their mechanism-based design make these attractive antiviral candidates.