The emergence of multidrug-resistant influenza viruses poses a persistent threat to public health. The current prophylaxis and therapeutic interventions for influenza virus infection have limited efficacy due to the continuous antigenic drift and antigenic shift of influenza viruses. As part of our ongoing effort to develop the next generation of influenza antivirals with broad-spectrum antiviral activity and a high genetic barrier to drug resistance, in this study we report the discovery of dapivirine, an FDA-approved HIV nonnucleoside reverse transcriptase inhibitor, as a broad-spectrum antiviral against multiple strains of influenza A and B viruses with low micromolar efficacy. Mechanistic studies revealed that dapivirine inhibits the nuclear entry of viral ribonucleoproteins at the early stage of viral replication. As a result, viral RNA and protein synthesis were inhibited. Furthermore, dapivirine has a high in vitro genetic barrier to drug resistance, and its antiviral activity is synergistic with oseltamivir carboxylate. In summary, the in vitro antiviral results of dapivirine suggest it is a promising candidate for the development of the next generation of dual influenza and HIV antivirals.

多药耐药性流感病毒的出现对公共健康构成了持续的威胁。由于流感病毒的连续抗原漂移和抗原转移，目前对流感病毒感染的预防和治疗干预具有有限的功效。作为我们开发具有广谱抗病毒活性和对耐药性具有高遗传屏障的下一代流感抗病毒药的持续努力的一部分，在这项研究中，我们报告发现了FDA批准的HIV非核苷逆转录酶抑制剂dapivirine的发现，一种广谱抗病毒药物，可抵抗多种具有低微摩尔功效的甲型和乙型流感病毒。机理研究表明，达比韦林在病毒复制的早期抑制病毒核糖核蛋白的核进入。因此，病毒RNA和蛋白质合成受到抑制。此外，达匹维林具有很高的体外对耐药性的遗传屏障，其抗病毒活性与奥司他韦羧酸盐具有协同作用。总之，达比韦林的体外抗病毒结果表明，它是下一代流感和艾滋病毒双重抗病毒药开发的有希望的候选者。