Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
Science. 2013 Apr 5;340(6128):71-5. doi: 10.1126/science.1232552. Epub 2013 Feb 21.
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.
流感抗病毒药物在调节疾病严重程度和控制大流行方面发挥着重要作用，而疫苗也在制备中，但像常用的神经氨酸酶抑制剂奥司他韦等药物的耐药性发展可能会限制它们未来的应用。我们在此报告一类新型的特异性、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物发挥作用，并且我们通过结构和机制研究证实了这种作用模式。这些化合物在细胞检测和动物模型中都具有作用，其功效可与神经氨酸酶抑制剂扎那米韦相当，并且对体外耐药株具有广谱活性。它们的结构与天然底物相似，设计基于机制，这使它们成为有吸引力的抗病毒候选药物。
