Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses.
Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses.
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针对大流行潜在 RNA 病毒的广谱抗病毒抑制剂。
DOI：
10.1101/2023.01.19.524824
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Sin
中科院分区：
文献类型：
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作者：
GarciaJr,Gustavo;Irudayam,JosephIgnatius;Jeyachandran,ArjitVijay;Dubey,Swati;Chang,Christina;Cario,SebastianCastillo;Price,Nate;Arumugam,Sathya;Marquez,AngelicaL;Shah,Aayushi;Fanaei,Amir;Chakravarty,Nikhil;Joshi,Shantanu;Sin
由于RNA病毒的快速进化，它们仍然是潜在大流行的明确和现实的威胁。为了减轻它们的影响，我们迫切需要能够抑制多个致病病毒家族的抗病毒剂，例如节肢动物传播和呼吸道病原体。增强宿主抗病毒途径可以在病毒感染升级为大爆发之前预防或限制病毒感染。因此，确定广谱抗病毒药物至关重要。我们已经测试了靶向病原体识别受体的先天免疫激动剂的小型文库，包括TLR、STING、NOD、Dectin和胞质DNA或RNA传感器。我们观察到TLR 3、STING、TLR 8和Dectin-1配体在不同程度上抑制虫媒病毒、基孔肯雅病毒（CHIKV）、西尼罗河病毒（WNV）和寨卡病毒。环二核苷酸（CDN）STING激动剂，如cAIMP，diABZI和2 '，3'-cGAMP，以及Dectin-1激动剂硬葡聚糖，表现出最有效的广谱抗病毒功能。比较转录组分析显示，CHIKV感染的细胞具有比WNV和ZIKV更多的差异表达基因。此外，基因表达分析表明，cAIMP治疗拯救了CHIKV诱导的细胞修复，免疫和代谢途径失调的细胞。此外，cAIMP在CHIKV-关节炎小鼠模型中提供针对CHIKV的保护。使用人心肌细胞证明了合成STING配体针对CHIKV、WNV、SARS-CoV-2和肠道病毒D 68（EV-D 68）感染的免疫保护作用。有趣的是，直接作用的抗病毒药物Remdesivir（一种核苷类似物）对CHIKV和WNV无效，但对SARS-CoV-2，RSV（呼吸道合胞病毒）和EV-D 68表现出有效的抗病毒作用。我们的研究确定了有效对抗多个大流行潜在RNA病毒家族的广谱抗病毒药物，这些药物可以快速部署以预防或减轻未来的大流行。
RNA viruses continue to remain a clear and present threat for potential pandemics due to their rapid evolution. To mitigate their impact, we urgently require antiviral agents that can inhibit multiple families of disease-causing viruses, such as arthropod-borne and respiratory pathogens. Potentiating host antiviral pathways can prevent or limit viral infections before escalating into a major outbreak. Therefore, it is critical to identify broad-spectrum antiviral agents. We have tested a small library of innate immune agonists targeting pathogen recognition receptors, including TLRs, STING, NOD, Dectin and cytosolic DNA or RNA sensors. We observed that TLR3, STING, TLR8 and Dectin-1 ligands inhibited arboviruses, Chikungunya virus (CHIKV), West Nile virus (WNV) and Zika virus, to varying degrees. Cyclic dinucleotide (CDN) STING agonists, such as cAIMP, diABZI, and 2’,3’-cGAMP, and Dectin-1 agonist scleroglucan, demonstrated the most potent, broad-spectrum antiviral function. Comparative transcriptome analysis revealed that CHIKV-infected cells had larger number of differentially expressed genes than of WNV and ZIKV. Furthermore, gene expression analysis showed that cAIMP treatment rescued cells from CHIKV-induced dysregulation of cell repair, immune, and metabolic pathways. In addition, cAIMP provided protection against CHIKV in a CHIKV-arthritis mouse model. Cardioprotective effects of synthetic STING ligands against CHIKV, WNV, SARS-CoV-2 and enterovirus D68 (EV-D68) infections were demonstrated using human cardiomyocytes. Interestingly, the direct-acting antiviral drug remdesivir, a nucleoside analogue, was not effective against CHIKV and WNV, but exhibited potent antiviral effects against SARS-CoV-2, RSV (respiratory syncytial virus), and EV-D68. Our study identifies broad-spectrum antivirals effective against multiple families of pandemic potential RNA viruses, which can be rapidly deployed to prevent or mitigate future pandemics.