Highly specific SARS-CoV-2 main protease (Mpro) mutations against the clinical antiviral ensitrelvir selected in a safe, VSV-based system

IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Antiviral research Pub Date : 2024-07-23 DOI:10.1016/j.antiviral.2024.105969
Stefanie Rauch , Francesco Costacurta , Helge Schöppe , Ju-Yi Peng , David Bante , Ela Emilie Erisoez , Bernhard Sprenger , Xi He , Seyed Arad Moghadasi , Laura Krismer , Anna Sauerwein , Anne Heberle , Toni Rabensteiner , Dai Wang , Andreas Naschberger , Theresia Dunzendorfer-Matt , Teresa Kaserer , Dorothee von Laer , Emmanuel Heilmann
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Abstract

In the SARS-CoV-2 pandemic, the so far two most effective approved antivirals are the protease inhibitors nirmatrelvir, in combination with ritonavir (Paxlovid) and ensitrelvir (Xocova). However, antivirals and indeed all antimicrobial drugs are sooner or later challenged by resistance mutations. Studying such mutations is essential for treatment decisions and pandemic preparedness. At the same time, generating resistant viruses to assess mutants is controversial, especially with pathogens of pandemic potential like SARS-CoV-2. To circumvent gain-of-function research with non-attenuated SARS-CoV-2, a previously developed safe system based on a chimeric vesicular stomatitis virus dependent on the SARS-CoV-2 main protease (VSV-Mpro) was used to select mutations against ensitrelvir. Ensitrelvir is clinically especially relevant due to its single-substance formulation, avoiding drug-drug interactions by the co-formulated CYP3A4 inhibitor ritonavir in Paxlovid. By treating VSV-Mpro with ensitrelvir, highly-specific resistant mutants against this inhibitor were selected, while being still fully or largely susceptible to nirmatrelvir. We then confirmed several ensitrelvir-specific mutants in gold standard enzymatic assays and SARS-CoV-2 replicons. These findings indicate that the two inhibitors can have distinct viral resistance profiles, which could determine treatment decisions.

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在基于 VSV 的安全系统中筛选出针对临床抗病毒药物 ensitrelvir 的高特异性 SARS-CoV-2 主要蛋白酶 (Mpro) 突变。
在 SARS-CoV-2 大流行的情况下,迄今为止已批准的两种最有效的抗病毒药物是蛋白酶抑制剂 nirmatrelvir(与利托那韦联用)(Paxlovid)和 ensitrelvir(Xocova)。然而,抗病毒药物乃至所有抗菌药物迟早都会受到抗药性突变的挑战。研究这种突变对治疗决策和大流行病防备至关重要。与此同时,产生抗药性病毒以评估突变体是有争议的,特别是对于像 SARS-CoV-2 这样具有大流行潜力的病原体。为了避免使用非减毒 SARS-CoV-2 进行功能增益研究,我们使用了以前开发的基于依赖 SARS-CoV-2 主蛋白酶的嵌合型水泡性口炎病毒(VSV-Mpro)的安全系统来选择抗 Ensitrelvir 的突变体。Ensitrelvir 在临床上具有特别重要的意义,因为它采用单一药物制剂,避免了 Paxlovid 中共同配制的 CYP3A4 抑制剂利托那韦的药物相互作用。通过用恩西特韦处理 VSV-Mpro,我们筛选出了几种对这种抑制剂具有高度特异性耐药性的突变体,而它们对尼马特韦仍然完全或基本敏感。然后,我们在金标准酶测定和 SARS-CoV-2 复制子中证实了几种 ensitrelvir 特异性突变体。这些研究结果表明,这两种抑制剂可能具有不同的病毒耐药性特征,从而决定治疗方案。
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来源期刊
Antiviral research
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.
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