Orally bioavailable RORγ/DHODH dual host-targeting small molecules with broad-spectrum antiviral activity

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research Pub Date : 2024-09-19 DOI:10.1016/j.antiviral.2024.106008

Alexandra Herrmann , Christian Gege , Christina Wangen , Sabrina Wagner , Melanie Kögler , Arne Cordsmeier , Pascal Irrgang , Wing-Hang Ip , Tatjana Weil , Victoria Hunszinger , Rüdiger Groß , Natalie Heinen , Stephanie Pfaender , Sebastian Reuter , Robert Klopfleisch , Nadja Uhlig , Valentina Eberlein , Leila Issmail , Thomas Grunwald , Benjamin Hietel , Friedrich Hahn

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引用次数: 0

Abstract

Host-directed antivirals (HDAs) represent an attractive treatment option and a strategy for pandemic preparedness, especially due to their potential broad-spectrum antiviral activity and high barrier to resistance development. Particularly, dual-targeting HDAs offer a promising approach for antiviral therapy by simultaneously disrupting multiple pathways essential for viral replication.

Izumerogant (IMU-935) targets two host proteins, (i) the retinoic acid receptor-related orphan receptor γ isoform 1 (RORγ1), which modulates cellular cholesterol metabolism, and (ii) the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in de novo pyrimidine synthesis. Here, we synthesized optimized derivatives of izumerogant and characterized their antiviral activity in comparison to a recently described structurally distinct RORγ/DHODH dual inhibitor. Cell culture-based infection models for enveloped and non-enveloped DNA and RNA viruses, as well as a retrovirus, demonstrated high potency and broad-spectrum activity against human viral pathogens for RORγ/DHODH dual inhibitors at nanomolar concentrations. Comparative analyses with equipotent single-target inhibitors in metabolite supplementation approaches revealed that the dual-targeting mode represents the mechanistic basis for the potent antiviral activity. For SARS-CoV-2, an optimized dual inhibitor completely blocked viral replication in human airway epithelial cells at 5 nM and displayed a synergistic drug interaction with the nucleoside analog molnupiravir. In a SARS-CoV-2 mouse model, treatment with a dual inhibitor alone, or in combination with molnupiravir, reduced the viral load by 7- and 58-fold, respectively.

Considering the clinical safety, oral bioavailability, and tolerability of izumerogant in a recent Phase I study, izumerogant-like drugs represent potent dual-targeting antiviral HDAs with pronounced broad-spectrum activity for further clinical development.

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具有广谱抗病毒活性的口服生物活性 RORγ/DHODH 双宿主靶向小分子。

宿主定向抗病毒药物（HDAs）是一种极具吸引力的治疗选择，也是大流行病防备战略的一种，特别是因为它们具有潜在的广谱抗病毒活性和高抗药性发展屏障。特别是，双靶向 HDAs 通过同时破坏病毒复制所必需的多种途径，为抗病毒治疗提供了一种前景广阔的方法。Izumerogant（IMU-935）靶向两种宿主蛋白：(i) 视黄酸受体相关孤儿受体γ异构体1（RORγ1），它调节细胞胆固醇代谢；(ii) 二氢烟酸脱氢酶（DHODH），它参与嘧啶的从头合成。在这里，我们合成了优化的 izumerogant 衍生物，并将其抗病毒活性与最近描述的一种结构独特的 RORγ/DHODH 双抑制剂进行了比较。基于细胞培养的包膜和非包膜 DNA 和 RNA 病毒以及逆转录病毒感染模型表明，纳摩尔浓度的 RORγ/DHODH 双抑制剂对人类病毒病原体具有高效力和广谱活性。在代谢物补充方法中与等效单靶点抑制剂的比较分析表明，双靶点模式代表了强效抗病毒活性的机理基础。对于 SARS-CoV-2 病毒，一种优化的双重抑制剂在 5 nM 的浓度下就能完全阻断病毒在人气道上皮细胞中的复制，并与核苷类似物莫仑吡韦有协同作用。在 SARS-CoV-2 小鼠模型中，单独使用双重抑制剂或与莫仑吡韦联合使用可使病毒载量分别减少 7 倍和 58 倍。考虑到 izumerogant 在近期 I 期研究中的临床安全性、口服生物利用度和耐受性，izumerogant 类药物代表了具有明显广谱活性的强效双靶点抗病毒 HDA，可用于进一步的临床开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Antiviral research 医学-病毒学

CiteScore

17.10

自引率

3.90%

发文量

157

审稿时长

34 days

期刊介绍： Antiviral Research is a journal that focuses on various aspects of controlling viral infections in both humans and animals. It is a platform for publishing research reports, short communications, review articles, and commentaries. The journal covers a wide range of topics including antiviral drugs, antibodies, and host-response modifiers. These topics encompass their synthesis, in vitro and in vivo testing, as well as mechanisms of action. Additionally, the journal also publishes studies on the development of new or improved vaccines against viral infections in humans. It delves into assessing the safety of drugs and vaccines, tracking the evolution of drug or vaccine-resistant viruses, and developing effective countermeasures. Another area of interest includes the identification and validation of new drug targets. The journal further explores laboratory animal models of viral diseases, investigates the pathogenesis of viral diseases, and examines the mechanisms by which viruses avoid host immune responses.