Meineke Robert, Stelz Sonja, Busch Maximilian, Werlein Christopher, Kühnel Mark, Jonigk Danny, Rimmelzwaan Guus F, Elbahesh Husni
Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine in Hannover (TiHo), Bünteweg 17, 30559 Hannover, Germany.
Department of Pathology, Hannover Medical School (MHH), Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
iScience. 2023 Feb 28;26(4):106309. doi: 10.1016/j.isci.2023.106309. eCollection 2023 Apr 21.
Influenza viruses (IVs) cause substantial global morbidity and mortality. Given the limited range of licensed antiviral drugs and their reduced efficacy due to resistance mutations, repurposing FDA-approved kinase inhibitors as fast-tracked host-targeted antivirals is an attractive strategy. We identified six FDA-approved non-receptor tyrosine kinase-inhibitors (NRTKIs) as potent inhibitors of viral replication of pandemic and seasonal IVs . We validated their efficacy in a biologically and clinically relevant model of human precision-cut lung slices. We identified steps of the virus infection cycle affected by these inhibitors and assessed their effect(s) on host responses. Their overlapping targets suggest crosstalk between Abl, EGFR, and PDGFR pathways during IAV infection. Our data and established safety profiles of these NRTKIs provide compelling evidence for further clinical investigations and repurposing as host-targeted influenza antivirals. Moreover, these NRTKIs have broad-spectrum antiviral potential given that their kinase/pathway targets are critical for the replication of many viruses.
流感病毒（IVs）在全球范围内导致大量发病和死亡。鉴于已获许可的抗病毒药物种类有限，且由于耐药性突变其疗效降低，将美国食品药品监督管理局（FDA）批准的激酶抑制剂重新用作快速推进的宿主靶向抗病毒药物是一种有吸引力的策略。我们确定了六种FDA批准的非受体酪氨酸激酶抑制剂（NRTKIs）作为大流行和季节性流感病毒复制的有效抑制剂。我们在具有生物学和临床相关性的人类精密切割肺切片模型中验证了它们的疗效。我们确定了受这些抑制剂影响的病毒感染周期步骤，并评估了它们对宿主反应的影响。它们重叠的靶点表明甲型流感病毒（IAV）感染期间Abl、表皮生长因子受体（EGFR）和血小板衍生生长因子受体（PDGFR）途径之间存在串扰。我们的数据以及这些NRTKIs已确立的安全性概况为进一步的临床研究和重新用作宿主靶向流感抗病毒药物提供了有力证据。此外，鉴于这些NRTKIs的激酶/途径靶点对许多病毒的复制至关重要，它们具有广谱抗病毒潜力。
