Bithiazole inhibitors of PI4KB show broad-spectrum antiviral activity against different viral families

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY Antiviral research Pub Date : 2024-09-10 DOI:10.1016/j.antiviral.2024.106003

Maria Grazia Martina , Vincent Carlen , Sarah Van der Reysen , Elena Bianchi , Noemi Cabella , Emmanuele Crespan , Marco Radi , Valeria Cagno

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Abstract

Broad-spectrum antivirals can be extremely important for pandemic preparedness. Targeting host factors dispensable for the host but indispensable for the virus can result in high barrier to resistance and a large range of viruses targeted. PI4KB is a lipid kinase involved in the replication of several RNA viruses, but common inhibitors of this target are mainly active against members of the Picornaviridae family. Herein we describe the optimization of bithiazole PI4KB inhibitors as broad-spectrum antivirals (BSAs) active against different members of the Picornaviridae, Coronaviridae, Flaviviridae and Poxviridae families. Since some of these viruses are transmitted via respiratory route, the efficacy of one of the most promising compounds was evaluated in an airway model. The molecule showed complete viral inhibition and absence of toxicity. These results pave the road for the development of new BSAs.

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PI4KB 双噻唑抑制剂对不同病毒科具有广谱抗病毒活性

广谱抗病毒药物对防范大流行病极为重要。针对对宿主来说可有可无但对病毒来说不可或缺的宿主因子，可以产生很高的抗药性屏障，并能针对多种病毒。PI4KB 是一种脂质激酶，参与了多种 RNA 病毒的复制，但针对这一靶点的常见抑制剂主要对 Picornaviridae 家族成员有效。在本文中，我们介绍了双噻唑类 PI4KB 抑制剂作为广谱抗病毒药物（BSAs）的优化情况，这些药物对 Picornaviridae、Coronaviridae、Flaviviridae 和 Poxviridae 家族的不同成员都有活性。由于其中一些病毒通过呼吸道传播，因此在气道模型中对其中一种最有前景的化合物进行了药效评估。该分子对病毒有完全抑制作用，且无毒性。这些结果为开发新的 BSA 铺平了道路。

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.