治疗COVID-19的抗病毒药物仍然稀缺。卟啉和卟啉衍生物(PD)通常具有广谱抗病毒活性,具有低的耐药性发展风险。事实上,一些PDs在临床上被批准用于抗癌光动力疗法,重新利用临床批准的PDs可能是治疗COVID-19的替代方法.这里,我们表征了替莫芬的能力,维替泊芬,talaporfin和redaporfin灭活SARS-CoV-2感染颗粒。评估了PDs对SARS-CoV-2感染性的光依赖性和非依赖性作用。PDs光活化以非常低的浓度和轻剂量成功地灭活了SARS-CoV-2。然而,只有替莫芬和维替泊芬在黑暗中灭活了SARS-CoV-2,是最有效的。PDs治疗降低了感染的Caco-2细胞中的病毒载量,而不诱导细胞毒性。此外,替莫芬和维替泊芬的光依赖性治疗作用于病毒感染的早期阶段。使用脂质载体作为膜模型,我们表征了PD与病毒包膜的相互作用。Verteporfin对病毒灭活的IC50最低,对脂质双层的分配系数(Kp)最高。奇怪的是,尽管替莫芬和redaporfin表现出相似的Kps,redaporfin没有光依赖性的抗病毒活性,只有替莫芬和维替泊芬引起了脂质膜紊乱。事实上,redaporfin位于更靠近双层表面,而替莫芬和维替波芬位于更靠近中心的位置。我们的结果表明,病毒包膜亲和力,随着脂质双层的渗透和不稳定,似乎对介导PDs抗病毒活性至关重要。总之,这些发现为替莫芬和维替泊芬在COVID-19的全身治疗中的标签外应用开辟了新的途径。
Antiviral medicines to treat COVID-19 are still scarce. Porphyrins and porphyrin derivatives (PDs) usually present broad-spectrum antiviral activity with low risk of resistance development. In fact, some PDs are clinically approved to be used in anti-cancer photodynamic therapy and repurposing clinically approved PDs might be an alternative to treat COVID-19. Here, we characterize the ability of temoporfin, verteporfin, talaporfin and redaporfin to inactivate SARS-CoV-2 infectious particles. PDs light-dependent and -independent effect on SARS-CoV-2 infectivity were evaluated. PDs photoactivation successfully inactivated SARS-CoV-2 with very low concentrations and light dose. However, only temoporfin and verteporfin inactivated SARS-CoV-2 in the dark, being verteporfin the most effective. PDs treatment reduced viral load in infected Caco-2 cells, while not inducing cytotoxicity. Furthermore, light-independent treatment with temoporfin and verteporfin act on early stages of viral infection. Using lipid vehicles as membrane models, we characterized PDs interaction to the viral envelope. Verteporfin presented the lowest IC50 for viral inactivation and the highest partition coefficients (Kp) towards lipid bilayers. Curiously, although temoporfin and redaporfin presented similar Kps, redaporfin did not present light-independent antiviral activity, and only temoporfin and verteporfin caused lipid membrane disorder. In fact, redaporfin is located closer to the bilayer surface, while temoporfin and verteporfin are located closer to the centre. Our results suggest that viral envelope affinity, with penetration and destabilization of the lipid bilayer, seems critical to mediate PDs antiviral activity. Altogether, these findings open new avenues for the off-label application of temoporfin and verteporfin in the systemic treatment of COVID-19.