鉴定针对拉沙病毒聚合酶的大环化合物

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research Pub Date : 2024-06-04 DOI:10.1016/j.antiviral.2024.105923

Virginia Aida-Ficken , Jamie A. Kelly , Payel Chatterjee , M. Harley Jenks , Laura K. McMullan , César G. Albariño , Joel M. Montgomery , Katherine L. Seley-Radtke , Christina F. Spiropoulou , Mike Flint

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引用次数: 0

摘要

目前还没有针对拉沙病毒（LASV）感染的获批疫苗或疗法。为了找出具有抗拉沙病毒活性的化合物，我们在生物安全等级 4 级的条件下开展了一项基于细胞的筛选活动，并测试了近 60,000 种化合物对传染性报告基因拉沙病毒的活性。筛选出的新化合物包括几种结构相关的大环化合物。其中最有效的是 Mac128，它对报告病毒的半数致死浓度（EC50）为亚微摩尔，可抑制野生型 IV 族 LASV，并将病毒滴度降低 4 个数量级。机理研究表明，Mac128 可在聚合酶水平上抑制病毒复制。

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Identification of a macrocyclic compound targeting the lassa virus polymerase

There are no approved vaccines or therapeutics for Lassa virus (LASV) infections. To identify compounds with anti-LASV activity, we conducted a cell-based screening campaign at biosafety level 4 and tested almost 60,000 compounds for activity against an infectious reporter LASV. Hits from this screen included several structurally related macrocycles. The most potent, Mac128, had a sub-micromolar EC₅₀ against the reporter virus, inhibited wild-type clade IV LASV, and reduced viral titers by 4 orders of magnitude. Mechanistic studies suggested that Mac128 inhibited viral replication at the level of the polymerase.

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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.