Mutations in spike protein and allele variations in ACE2 impact targeted therapy strategies against SARS-CoV-2
| Autor: | Cheng Deng, Chuanjun Shu, Ding-Ding Mo, Xuan Huang, Jian-Wei Zhou, Huihao Tang |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) medicine.medical_treatment ACE2 Spike protein Biology Article Targeted therapy 03 medical and health sciences 0302 clinical medicine lcsh:Zoology medicine Receptor-ligand docking Humans Point Mutation lcsh:QL1-991 030212 general & internal medicine Allele Alleles Ecology Evolution Behavior and Systematics Ecology SARS-CoV-2 COVID-19 Spike Protein Virology 030104 developmental biology Spike Glycoprotein Coronavirus Animal Science and Zoology Drug therapy Angiotensin-Converting Enzyme 2 hormones hormone substitutes and hormone antagonists Protein Binding |
| Zdroj: | Zoological Research Zoological Research, Vol 42, Iss 2, Pp 170-181 (2021) |
| ISSN: | 2095-8137 |
| DOI: | 10.24272/j.issn.2095-8137.2020.301 |
| Popis: | Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly worldwide with high rates of transmission and substantial mortality. To date, however, no effective treatments or enough vaccines for COVID-19 are available. The roles of angiotensin converting enzyme 2 (ACE2) and spike protein in the treatment of COVID-19 are major areas of research. In this study, we explored the potential of ACE2 and spike protein as targets for the development of antiviral agents against SARS-CoV-2. We analyzed clinical data, genetic data, and receptor binding capability. Clinical data revealed that COVID-19 patients with comorbidities related to an abnormal renin-angiotensin system exhibited more early symptoms and poorer prognoses. However, the relationship between ACE2 expression and COVID-19 progression is still not clear. Furthermore, if ACE2 is not a good targetable protein, it would not be applicable across a wide range of populations. The spike-S1 receptor-binding domain that interacts with ACE2 showed various amino acid mutations based on sequence analysis. We identified two spike-S1 point mutations (V354F and V470A) by receptor-ligand docking and binding enzyme-linked immunosorbent assays. These variants enhanced the binding of the spike protein to ACE2 receptors and were potentially associated with increased infectivity. Importantly, the number of patients infected with the V354F and V470A mutants has increased with the development of the SARS-CoV-2 pandemic. These results suggest that ACE2 and spike-S1 are likely not ideal targets for the design of peptide drugs to treat COVID-19 in different populations.新型冠状病毒肺炎(COVID-19)是由严重急性呼吸系统综合征冠状病毒2 (SARS-CoV-2)引起的一种大流行疾病，目前正在全球范围内迅速蔓延，其传播速度快，死亡人数高。迄今为止，尚无针对COVID-19的有效治疗或疫苗。血管紧张素转化酶2 (ACE2)和刺突蛋白（spike）在COVID-19治疗中的作用是当前的研究重点。在本研究中，我们探索了ACE2和spike作为靶点开发抗SARS-CoV-2病毒药物的潜力。我们分析了临床数据、测序数据和受体结合能力。其中，临床资料显示，COVID-19合并肾素-血管紧张素系统异常的患者早期症状多，预后差。然而，ACE2表达水平与COVID-19进展之间的关系尚不清楚。因此，ACE2可能不是一个很好的靶标适用于治疗不同人群的COVID-19。根据序列分析，与ACE2相互作用的spike-S1受体结合区域有许多氨基酸突变。通过受体-配体对接和ELISA试验，我们鉴定了两个spike-S1点突变体(V354F和V470A)。这些变异增强了spike蛋白与ACE2受体的结合，可能与突变体传染性增加有关。更重要的是，随着SARS-CoV-2的流行，感染V354F或V470A突变体的患者数量正在增加。这些结果表明，ACE2和spike-S1可能不适用设计广泛用于治疗不同人群COVID-19的药物理想靶点。. |
| Databáze: | OpenAIRE |
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