Bereczki Ilona, Papp Henrietta, Kuczmog Anett, Madai Mónika, Nagy Veronika, Agócs Attila, Batta Gyula, Milánkovits Márton, Ostorházi Eszter, Mitrović Ana, Kos Janko, Zsigmond Áron, Hajdú István, Lőrincz Zsolt, Bajusz Dávid, Keserű György Miklós, Hodek Jan, Weber Jan, Jakab Ferenc, Herczegh Pál, Borbás Anikó
Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary.
Szentágothai Research Centre, National Laboratory of Virology, Ifjúság útja 20, H-7624 Pécs, Hungary.
Pharmaceuticals (Basel). 2021 Oct 30;14(11):1111. doi: 10.3390/ph14111111.
The protracted global COVID-19 pandemic urges the development of new drugs against the causative agent SARS-CoV-2. The clinically used glycopeptide antibiotic, teicoplanin, emerged as a potential antiviral, and its efficacy was improved with lipophilic modifications. This prompted us to prepare new lipophilic apocarotenoid conjugates of teicoplanin, its pseudoaglycone and the related ristocetin aglycone. Their antiviral effect was tested against SARS-CoV-2 in Vero E6 cells, using a cell viability assay and quantitative PCR of the viral RNA, confirming their micromolar inhibitory activity against viral replication. Interestingly, two of the parent apocarotenoids, bixin and β-apo-8'carotenoic acid, exerted remarkable anti-SARS-CoV-2 activity. Mechanistic studies involved cathepsin L and B, as well as the main protease 3CLPro, and the results were rationalized by computational studies. Glycopeptide conjugates show dual inhibitory action, while apocarotenoids have mostly cathepsin B and L affinity. Since teicoplanin is a marketed antibiotic and the natural bixin is an approved, cheap and widely used red colorant food additive, these readily available compounds and their conjugates as potential antivirals are worthy of further exploration.
旷日持久的全球新冠疫情促使人们研发针对病原体严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的新药。临床使用的糖肽类抗生素替考拉宁成为一种潜在的抗病毒药物，其疗效通过亲脂性修饰得到了提高。这促使我们制备替考拉宁、其假苷元和相关的瑞斯托菌素苷元的新型亲脂性类胡萝卜素缀合物。使用细胞活力测定法和病毒RNA定量PCR，在非洲绿猴肾细胞（Vero E6）中测试了它们对SARS-CoV-2的抗病毒作用，证实了它们对病毒复制具有微摩尔级的抑制活性。有趣的是，两种母体类胡萝卜素，即胭脂树橙和β-阿朴-8'-胡萝卜酸，表现出显著的抗SARS-CoV-2活性。机制研究涉及组织蛋白酶L和B以及主要蛋白酶3CLPro，计算研究对结果进行了合理化分析。糖肽缀合物表现出双重抑制作用，而类胡萝卜素主要与组织蛋白酶B和L具有亲和力。由于替考拉宁是一种上市抗生素，天然的胭脂树橙是一种经批准的、廉价且广泛使用的红色食用色素添加剂，这些容易获得的化合物及其缀合物作为潜在的抗病毒药物值得进一步探索。
