Parigger Lena, Krassnigg Andreas, Schopper Tobias, Singh Amit, Tappler Katharina, Köchl Katharina, Hetmann Michael, Gruber Karl, Steinkellner Georg, Gruber Christian C
Innophore GmbH, Graz, Austria.
Institute of Molecular Biosciences, University of Graz, Graz, Austria.
Front Med (Lausanne). 2022 Dec 14;9:1061142. doi: 10.3389/fmed.2022.1061142. eCollection 2022.
The current coronavirus pandemic is being combated worldwide by nontherapeutic measures and massive vaccination programs. Nevertheless, therapeutic options such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main-protease (M) inhibitors are essential due to the ongoing evolution toward escape from natural or induced immunity. While antiviral strategies are vulnerable to the effects of viral mutation, the relatively conserved M makes an attractive drug target: Nirmatrelvir, an antiviral targeting its active site, has been authorized for conditional or emergency use in several countries since December 2021, and a number of other inhibitors are under clinical evaluation. We analyzed recent SARS-CoV-2 genomic data, since early detection of potential resistances supports a timely counteraction in drug development and deployment, and discovered accelerated mutational dynamics of M since early December 2021.
We performed a comparative analysis of 10.5 million SARS-CoV-2 genome sequences available by June 2022 at GISAID to the NCBI reference genome sequence NC_045512.2. Amino-acid exchanges within high-quality regions in 69,878 unique M sequences were identified and time- and in-depth sequence analyses including a structural representation of mutational dynamics were performed using in-house software.
The analysis showed a significant recent event of mutational dynamics in M. We report a remarkable increase in mutational variability in an eight-residue long consecutive region (R188-G195) near the active site since December 2021.
The increased mutational variability in close proximity to an antiviral-drug binding site as described herein may suggest the onset of the development of antiviral resistance. This emerging diversity urgently needs to be further monitored and considered in ongoing drug development and lead optimization.
目前，全球正在通过非治疗性措施和大规模疫苗接种计划抗击新冠疫情。然而，由于病毒不断进化以逃避天然免疫或诱导免疫，诸如严重急性呼吸综合征冠状病毒2（SARS-CoV-2）主蛋白酶（M）抑制剂等治疗选择至关重要。虽然抗病毒策略容易受到病毒突变的影响，但相对保守的M蛋白成为一个有吸引力的药物靶点：靶向其活性位点的抗病毒药物奈玛特韦自2021年12月以来已在多个国家获得有条件或紧急使用授权，其他一些抑制剂也正在进行临床评估。我们分析了近期的SARS-CoV-2基因组数据，因为早期发现潜在耐药性有助于在药物研发和应用中及时采取应对措施，并且发现自2021年12月初以来M蛋白的突变动态加速。
我们将2022年6月前在全球共享流感数据倡议组织（GISAID）获取的1050万个SARS-CoV-2基因组序列与美国国立生物技术信息中心（NCBI）的参考基因组序列NC_045512.2进行了比较分析。在69878个独特的M蛋白序列的高质量区域内鉴定氨基酸交换情况，并使用内部软件进行时间和深度序列分析，包括突变动态的结构表示。
分析显示近期M蛋白发生了显著的突变动态事件。我们报告称，自2021年12月以来，活性位点附近一个八残基长的连续区域（R188 - G195）的突变变异性显著增加。
本文所述的抗病毒药物结合位点附近的突变变异性增加可能表明抗病毒耐药性开始出现。这种新出现的多样性迫切需要在正在进行的药物研发和先导化合物优化中进一步监测和考虑。
