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IMU-838, a Developmental DHODH Inhibitor in Phase II for Autoimmune Disease, Shows Anti-SARS-CoV-2 and Broad-Spectrum Antiviral Efficacy In Vitro
Viruses ( IF 3.8 ) Pub Date : 2020-12-05 , DOI: 10.3390/v12121394
Friedrich Hahn , Christina Wangen , Sigrun Häge , Antonia Sophia Peter , Gerhard Dobler , Brett Hurst , Justin Julander , Jonas Fuchs , Zsolt Ruzsics , Klaus Überla , Hans-Martin Jäck , Roger Ptak , Andreas Muehler , Manfred Gröppel , Daniel Vitt , Evelyn Peelen , Hella Kohlhof , Manfred Marschall

The ongoing pandemic spread of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) demands skillful strategies for novel drug development, drug repurposing and cotreatments, in particular focusing on existing candidates of host-directed antivirals (HDAs). The developmental drug IMU-838, currently being investigated in a phase 2b trial in patients suffering from autoimmune diseases, represents an inhibitor of human dihydroorotate dehydrogenase (DHODH) with a recently proven antiviral activity in vitro and in vivo. Here, we established an analysis system for assessing the antiviral potency of IMU-838 and DHODH-directed back-up drugs in cultured cell-based infection models. By the use of SARS-CoV-2-specific immunofluorescence, Western blot, in-cell ELISA, viral yield reduction and RT-qPCR methods, we demonstrated the following: (i) IMU-838 and back-ups show anti-SARS-CoV-2 activity at several levels of viral replication, i.e., protein production, double-strand RNA synthesis, and release of infectious virus; (ii) antiviral efficacy in Vero cells was demonstrated in a micromolar range (IMU-838 half-maximal effective concentration, EC50, of 7.6 ± 5.8 µM); (iii) anti-SARS-CoV-2 activity was distinct from cytotoxic effects (half-cytotoxic concentration, CC50, >100 µM); (iv) the drug in vitro potency was confirmed using several Vero lineages and human cells; (v) combination with remdesivir showed enhanced anti-SARS-CoV-2 activity; (vi) vidofludimus, the active determinant of IMU-838, exerted a broad-spectrum activity against a selection of major human pathogenic viruses. These findings strongly suggest that developmental DHODH inhibitors represent promising candidates for use as anti-SARS-CoV-2 therapeutics.

中文翻译:

IMU-838是一种针对自身免疫性疾病的II期发育型DHODH抑制剂,可显示抗SARS-CoV-2和广谱抗病毒功效

严重的2型严重急性呼吸系统综合症冠状病毒(SARS-CoV-2)的持续大流行传播要求新药开发,药物再利用和共同治疗的熟练策略,特别是针对宿主定向抗病毒药(HDA)的现有候选药物。目前正在2b期临床试验中针对自身免疫性疾病的患者开发的开发药物IMU-838代表了人二氢乳清酸脱氢酶(DHODH)的抑制剂,该抑制剂在体外体内均具有最近被证明的抗病毒活性。在这里,我们建立了一个分析系统,用于评估在培养的基于细胞的感染模型中IMU-838和DHODH指导的备用药物的抗病毒效力。通过使用SARS-CoV-2特异性免疫荧光,蛋白质印迹,细胞内ELISA,降低病毒产量和RT-qPCR方法,我们证明了以下几点:(i)IMU-838和备用疫苗显示抗SARS- CoV-2在几种病毒复制水平上的活性,即蛋白质生产,双链RNA合成和传染性病毒的释放;(ii)在微摩尔范围内证明了对Vero细胞的抗病毒功效(IMU-838的最大有效浓度半数EC 50为7.6±5.8 µM);(iii)抗SARS-CoV-2活性不同于细胞毒性作用(半细胞毒性浓度,CC 50,> 100 µM);(iv)使用几种Vero谱系和人类细胞确认了药物的体外效能;(v)与雷姆昔韦联合使用显示出增强的抗SARS-CoV-2活性;(vi)IMU-838的活性决定因子维氟地草对某些主要的人类致病病毒具有广谱活性。这些发现强烈表明,发育中的DHODH抑制剂是有希望的候选物,可用作抗SARS-CoV-2治疗剂。
更新日期:2020-12-05
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