Multidrug Combinations against SARS-CoV-2 Using GS-441524 or Ivermectin with Molnupiravir and/or Nirmatrelvir in Reconstituted Human Nasal Airway Epithelia.

IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Denise Siegrist, Hulda R Jonsdottir, Mendy Bouveret, Bernadett Boda, Samuel Constant, Olivier B Engler
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Abstract

Background. The emergence, global spread, and persistence of SARS-CoV-2 resulted in an unprecedented need for effective antiviral drugs. Throughout the pandemic, various drug development and treatment strategies were adopted, including repurposing of antivirals designed for other viruses along with a multitude of other drugs with varying mechanisms of action (MoAs). Furthermore, multidrug treatment against COVID-19 is an ongoing topic and merits further investigation. Method/Objectives. We assessed the efficacy of multidrug treatment against SARS-CoV-2 in reconstituted human nasal epithelia, using combinations of molnupiravir and nirmatrelvir as a baseline, adding suboptimal concentrations of either GS-441524 or ivermectin, attempting to increase overall antiviral activity while lowering the overall therapeutic dose. Results. Nirmatrelvir combined with molnupiravir, GS-441524, or ivermectin at suboptimal concentrations show increased antiviral activity compared to single treatment. No triple combinations showed improved inhibition of SARS-CoV-2 replication beyond what was observed for double treatments. Conclusions. In general, we observed that the addition of a third compound is not beneficial for antiviral activity, while various double combinations exhibit increased antiviral activity over single treatment.

在重组人鼻气道上皮细胞中使用 GS-441524 或伊维菌素与 Molnupiravir 和/或 Nirmatrelvir 的多药联合疗法防治 SARS-CoV-2
背景。SARS-CoV-2 的出现、全球传播和持续存在导致了对有效抗病毒药物前所未有的需求。在整个疫情期间,采用了各种药物开发和治疗策略,包括重新利用为其他病毒设计的抗病毒药物以及具有不同作用机制(MoAs)的多种其他药物。此外,针对 COVID-19 的多药治疗也是一个正在进行的课题,值得进一步研究。方法/目标。我们在重组人鼻腔上皮细胞中评估了多种药物治疗 SARS-CoV-2 的疗效,以莫仑吡韦和尼尔马特韦组合为基线,加入次优浓度的 GS-441524 或伊维菌素,试图在降低总体治疗剂量的同时提高总体抗病毒活性。研究结果与单一治疗相比,尼尔马特韦与次优浓度的莫仑吡韦、GS-441524或伊维菌素联合治疗显示出更强的抗病毒活性。三联疗法对 SARS-CoV-2 复制的抑制作用均未超过双联疗法。结论。总的来说,我们观察到添加第三种化合物对抗病毒活性没有益处,而各种双联化合物的抗病毒活性比单药治疗有所提高。
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来源期刊
Pharmaceutics
Pharmaceutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍: Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications,  and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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