Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial.
Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial.
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DOI：
10.1038/s41467-022-34839-9
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发表时间：
2022-11-26
影响因子：
16.6
通讯作者：
Fletcher, Thomas
中科院分区：
文献类型：
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作者：
Donovan-Banfield, I'ah;Penrice-Randal, Rebekah;Goldswain, Hannah;Rzeszutek, Aleksandra M.;Pilgrim, Jack;Bullock, Katie;Saunders, Geoffrey;Northey, Josh;Dong, Xiaofeng;Ryan, Yan;Reynolds, Helen;Tetlow, Michelle;Walker, Lauren E.;FitzGerald, Richard;Hale, Colin;Lyon, Rebecca;Woods, Christie;Ahmad, Shazaad;Hadjiyiannakis, Dennis;Periselneris, Jimstan;Knox, Emma;Middleton, Calley;Lavelle-Langham, Lara;Shaw, Victoria;Greenhalf, William;Edwards, Thomas;Lalloo, David G.;Edwards, Christopher J.;Darby, Alistair C.;Carroll, Miles W.;Griffiths, Gareth;Khoo, Saye H.;Hiscox, Julian A.;Fletcher, Thomas
Molnupiravir是一种抗病毒药，目前已获英国药品和保健产品监管局（MHRA）批准用于治疗高风险的COVID-19患者，该药物在SARS-CoV-2中引起致命的错误灾难。这种药物诱导的作用机制如何影响耐药突变的出现尚不清楚。为了研究这一点，我们使用了来自AGILE候选人特异性试验（CST）-2（临床试验编号NCT 04746183）的样本。AGILE CST-2的主要结局是测量莫努匹韦在人体中的药物安全性和抗病毒疗效（180名受试者以1：1的比例随机分配安慰剂）。在这里，我们描述了CST-2的预先指定的探索性病毒学终点，即确定莫努匹韦治疗诱导的SARS-CoV-2中可能的基因组变化。我们使用高通量扩增子测序和微小变异分析来检测每个参与者的病毒基因组学，这些参与者的纵向样本（随机化后第1、3和5天）通过了病毒基因组质量标准（莫努匹韦n = 59，安慰剂n = 65）。在治疗过程中，没有特定突变与莫努匹韦治疗相关。我们发现，莫努匹拉韦显着增加转换：颠换突变比在SARS-CoV-2，与致命错误灾难的模型一致。这项研究强调了检查宿主内病毒种群的效用，以加强对潜在治疗后出现的适应的预测和监测。Molnupiravir是一种抗病毒药物，可导致SARS-CoV-2 RNA中的致命错误灾难。在这里，作者使用从英国AGILE IIa期临床试验中获得的样本证实了莫努匹拉韦在人体中的作用机制，该临床试验研究了该药物对SARS-CoV-2的抗病毒功效。未发现治疗相关的SARS-CoV-2突变。
Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)−2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations. Molnupiravir is an antiviral that forces lethal error catastrophe in SARS-CoV-2 RNAs. Here, the authors confirm the mechanism of action of molnupiravir in humans using samples obtained from the UK’s AGILE phase IIa clinical trial investigating the antiviral efficacy of the drug against SARS-CoV-2. No treatment-associated SARS-CoV-2 mutations were identified.
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影响因子：
16.6
作者：
Kokic G;Hillen HS;Tegunov D;Dienemann C;Seitz F;Schmitzova J;Farnung L;Siewert A;Höbartner C;Cramer P
通讯作者：
Cramer P
DOI：
10.1101/2021.03.13.435256
发表时间：
2021-05-11
影响因子：
11.1
作者：
Malone, Brandon;Chen, James;Campbell, Elizabeth A.
通讯作者：
Campbell, Elizabeth A.
摩尔班司米拉维尔诱导的SARS-COV-2诱变的机理。
影响因子：
16.8
作者：
Kabinger F;Stiller C;Schmitzová J;Dienemann C;Kokic G;Hillen HS;Höbartner C;Cramer P
通讯作者：
Cramer P
影响因子：
7.7
作者：
Tonkin-Hill G;Martincorena I;Amato R;Lawson ARJ;Gerstung M;Johnston I;Jackson DK;Park N;Lensing SV;Quail MA;Gonçalves S;Ariani C;Spencer Chapman M;Hamilton WL;Meredith LW;Hall G;Jahun AS;Chaudhry Y;Hosmillo M;Pinckert ML;Georgana I;Yakovleva A;Caller LG;Caddy SL;Feltwell T;Khokhar FA;Houldcroft CJ;Curran MD;Parmar S;COVID-19 Genomics UK (COG-UK) Consortium;Alderton A;Nelson R;Harrison EM;Sillitoe J;Bentley SD;Barrett JC;Torok ME;Goodfellow IG;Langford C;Kwiatkowski D;Wellcome Sanger Institute COVID-19 Surveillance Team
通讯作者：
Wellcome Sanger Institute COVID-19 Surveillance Team
DOI：
10.1016/j.jcv.2021.104993
发表时间：
2021-11
期刊：
Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
影响因子：
--
作者：
Coolen JPM;Wolters F;Tostmann A;van Groningen LFJ;Bleeker-Rovers CP;Tan ECTH;van der Geest-Blankert N;Hautvast JLA;Hopman J;Wertheim HFL;Rahamat-Langendoen JC;Storch M;Melchers WJG
通讯作者：
Melchers WJG