Severe emerging and re-emerging viral infections such as Lassa fever, Avian influenza (AI), and COVID-19 caused by SARS-CoV-2 urgently call for new strategies for the development of broad-spectrum antivirals targeting conserved components in the virus life cycle. Viral lipids are essential components, and viral-cell membrane fusion is the required entry step for most unrelated enveloped viruses. In this paper, we identified a porphyrin derivative of protoporphyrin IX (PPIX) that showed broad antiviral activities in vitro against a panel of enveloped pathogenic viruses including Lassa virus (LASV), Machupo virus (MACV), and SARS-CoV-2 as well as various subtypes of influenza A viral strains with IC₅₀ values ranging from 0.91±0.25 μM to 1.88±0.34 μM. A mechanistic study using influenza A/Puerto Rico/8/34 (H1N1) as a testing strain showed that PPIX inhibits the infection in the early stage of virus entry through biophysically interacting with the hydrophobic lipids of enveloped virions, thereby inhibiting the formation of the negative curvature required for fusion and blocking the entry of enveloped viruses into host cells. In addition, the preliminary antiviral activities of PPIX were further assessed by testing mice infected with the influenza A/Puerto Rico/8/34 (H1N1) virus. The results showed that compared with the control group without drug treatment, the survival rate and mean survival time of the mice treated with PPIX were apparently prolonged. These data encourage us to conduct further investigations using PPIX as a lead compound for the rational design of lipid-targeting antivirals for the treatment of infection with enveloped viruses.

中文翻译：

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原卟啉的广谱抗病毒药抑制高致病性新兴病毒的进入

SARS-CoV-2引起的严重新兴病毒和新兴病毒感染，例如拉沙热，禽流感（AI）和COVID-19，迫切需要开发针对病毒生命中保守成分的广谱抗病毒药物的新策略周期。病毒脂质是必不可少的成分，对于大多数不相关的包膜病毒，病毒细胞膜融合是必需的进入步骤。在本文中，我们鉴定了原卟啉IX（PPIX）的卟啉衍生物，该衍生物在体外对一组包膜的致病病毒包括Lassa病毒（LASV），Machupo病毒（MACV）和SARS-CoV-2也具有广泛的抗病毒活性。具有IC _50的各种A型流感病毒亚型值范围从0.91±0.25μM到1.88±0.34μM。使用甲型流感病毒/波多黎各/ 8/34（H1N1）流感病毒作为测试菌株的机理研究表明，PPIX通过与包膜病毒颗粒的疏水脂质发生生物物理相互作用而抑制了病毒进入的早期感染，从而抑制了病毒的形成。融合并阻止包膜病毒进入宿主细胞所需的负曲率。此外，通过测试感染了A / Puerto Rico / 8/34（H1N1）流感病毒的小鼠，进一步评估了PPIX的初步抗病毒活性。结果显示，与未进行药物治疗的对照组相比，PPIX治疗的小鼠的存活率和平均存活时间显然延长了。这些数据鼓励我们使用PPIX作为先导化合物进行进一步研究，以合理设计靶向脂质的抗病毒药物，以治疗包膜病毒感染。