Polyphenylene carboxymethylene (PPCM) microbicide repurposed as antiviral against SARS-CoV-2. Proof of concept in primary human undifferentiated epithelial cells.
Polyphenylene carboxymethylene (PPCM) microbicide repurposed as antiviral against SARS-CoV-2. Proof of concept in primary human undifferentiated epithelial cells.
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DOI：
10.1016/j.antiviral.2021.105162
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发表时间：
2021-10
影响因子：
7.6
通讯作者：
Freiberg AN
中科院分区：
文献类型：
--
作者：
Escaffre O;Freiberg AN
截至2021年8月，严重急性呼吸综合征冠状病毒2(SARS-CoV-2)已感染全球2亿多人。目前还没有批准的治疗方法能够从由SARS-CoV-2引起的2019年严重冠状病毒病(新冠肺炎)病例中提供高康复机会，并且只有在发病早期使用雷米西韦和被动免疫疗法才能看到有益效果。变种的出现也引起了人们对抗体疗法、抗病毒药物和疫苗有效性的担忧。因此，仍有必要开发新的抗病毒药物。在这里，我们研究了原代培养的人气管/支气管上皮细胞(NHBE)和小气道上皮细胞(SAEC)是否适合作为SARS-CoV-2感染的肺部模型，以确定杀菌剂聚苯二甲亚甲基(PPCM)是否具有抗SARS-CoV-2的活性。NHBE和SAEC都表达病毒进入肺上皮细胞所需的蛋白质。然而，这些细胞对SARS-CoV-2的耐受性只是低到中等，因为在8天的动力学过程中，滴度最多增加了2.5log10。与NHBE不同，SAEC的复制水平与使用人类正常组织或气液界面培养的其他研究的数据一致，这表明SAEC可能比NHBE更适合用于药物筛选。PPCM对SARS-CoV-2的EC50在32到132g/ml之间，选择性指数在12到41之间，这取决于细胞类型和使用的感染剂量。PPCM的剂量与之前显示的对其他人类病毒有效的剂量一致。最后，在SAEC中观察到的PPCM抗病毒作用与在重症新冠肺炎患者中观察到的过度表达的炎症标志物的减少是一致的。总之，我们的数据支持这样一个事实，即PPCM应该在体内进一步评估其对SARS-CoV-2的毒性和抗病毒活性。
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has infected over 200 million people throughout the world as of August 2021. There are currently no approved treatments providing high chance of recovery from a severe case of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, and the beneficial effect of Remdesivir and passive immunization therapies may only be seen when administered early on disease onset. The emergence of variants is also raising concerns regarding the efficacy of antibody therapies, antivirals, and vaccines. Therefore, there is still a need to develop new antivirals. Here, we investigated the suitability of primary human epithelial cells from the trachea/bronchia (NHBE) and small airway (SAEC) as lung models of SARS-CoV-2 infection to determine, whether the microbicide polyphenylene carboxymethylene (PPCM) has antiviral activity against SARS-CoV-2. Both NHBE and SAEC expressed proteins required for virus entry in lung epithelial cells. However, these cells were only low to moderately permissive to SARS-CoV-2 as titers increased at best by 2.5 log10 during an 8-day kinetic. Levels of replication in SAEC, unlike in NHBE, were consistent with data from other studies using human normal tissues or air-liquid interface cultures, suggesting that SAEC may be more relevant to use than NHBE for drug screening. PPCM EC50 against SARS-CoV-2 was between 32 and 132 μg/ml with a selectivity index between 12 and 41, depending on the cell type and the infective dose used. PPCM doses were consistent with those previously showing effect against other human viruses. Finally, PPCM antiviral effect observed in SAEC was in line with reduction of inflammatory markers observed overly expressed in severe COVID-19 patients. Altogether, our data support the fact that PPCM should be further evaluated in vivo for toxicity and antiviral activity against SARS-CoV-2.
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影响因子：
64.5
作者：
Hou, Yixuan J.;Okuda, Kenichi;Baric, Ralph S.
通讯作者：
Baric, Ralph S.
DOI：
10.1038/s41577-021-00522-1
发表时间：
2021-04
期刊：
Nature reviews. Immunology
影响因子：
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通讯作者：
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作者：
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通讯作者：
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影响因子：
168.9
作者：
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通讯作者：
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影响因子：
64.8
作者：
Hoffmann, Markus;Moesbauer, Kirstin;Poehlmann, Stefan
通讯作者：
Poehlmann, Stefan