Department of Physiological Sciences, University of Florida College of Veterinary Medicine, Gainesville, FL, USA.
Department of Geography and the Emerging Pathogens Institute, Spatial Epidemiology and Ecology Research Laboratory, University of Florida, Gainesville, FL, USA.
Biochem Biophys Res Commun. 2021 Jan 29;538:173-179. doi: 10.1016/j.bbrc.2020.11.095. Epub 2020 Dec 3.
There is an urgent need to identify therapies that prevent SARS-CoV-2 infection and improve the outcome of COVID-19 patients. Although repurposed drugs with favorable safety profiles could have significant benefit, widely available prevention or treatment options for COVID-19 have yet to be identified. Efforts to identify approved drugs with in vitro activity against SARS-CoV-2 resulted in identification of antiviral sigma-1 receptor ligands, including antihistamines in the histamine-1 receptor binding class. We identified antihistamine candidates for repurposing by mining electronic health records of usage in population of more than 219,000 subjects tested for SARS-CoV-2. Usage of diphenhydramine, hydroxyzine and azelastine was associated with reduced incidence of SARS-CoV-2 positivity in subjects greater than age 61. We found diphenhydramine, hydroxyzine and azelastine to exhibit direct antiviral activity against SARS-CoV-2 in vitro. Although mechanisms by which specific antihistamines exert antiviral effects is not clear, hydroxyzine, and possibly azelastine, bind Angiotensin Converting Enzyme-2 (ACE2) and the sigma-1 receptor as off-targets. Clinical studies are needed to measure the effectiveness of diphenhydramine, hydroxyzine and azelastine for disease prevention, for early intervention, or as adjuvant therapy for severe COVID-19.
目前迫切需要找到能够预防 SARS-CoV-2 感染并改善 COVID-19 患者预后的疗法。虽然具有良好安全性的已上市药物可能具有重要的治疗效果，但目前尚未找到广泛可用的 COVID-19 预防或治疗方法。人们致力于寻找具有抗 SARS-CoV-2 体外活性的已批准药物，由此发现了抗病毒 sigma-1 受体配体，包括组胺-1 受体结合类别的抗组胺药。我们通过挖掘 219000 多名接受 SARS-CoV-2 检测的受试者的电子健康记录，确定了可用于重新定位的抗组胺药候选药物。在年龄大于 61 岁的受试者中，发现使用苯海拉明、羟嗪和氮卓斯汀与 SARS-CoV-2 阳性率降低有关。我们发现苯海拉明、羟嗪和氮卓斯汀在体外对 SARS-CoV-2 具有直接的抗病毒活性。尽管特定抗组胺药发挥抗病毒作用的机制尚不清楚，但羟嗪和可能的氮卓斯汀作为非靶点与血管紧张素转换酶-2（ACE2）和 sigma-1 受体结合。需要开展临床研究来评估苯海拉明、羟嗪和氮卓斯汀在疾病预防、早期干预或作为严重 COVID-19 的辅助治疗方面的有效性。
