对抗SARS-CoV-2感染的新型尖端抑制剂的发现
Li-Te Tai1, Cheng-Yun Yeh2, Yu-Jen Chang3
1Industrial Development Graduate Program of College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300193, Taiwan.
International journal of molecular sciences
|June 19, 2024
概括
计算机辅助药物设计确定了强大的SARS-CoV-2尖端蛋白抑制剂. 化合物C8.2对SARS-CoV-2和Omicron变种表现出强烈的抗病毒活性,提供了一个有前途的治疗策略.
科学领域:
- 病毒学 病毒学
- 药物发现 药物发现 药物发现
- 计算化学的计算化学
背景情况:
- 严重急性呼吸系统综合征冠状病毒-2 (SARS-CoV-2) 驱动着全球大流行.
- 尖端蛋白-ACE2相互作用对于病毒进入至关重要,使其成为关键的治疗点.
- SARS-CoV-2 变种的快速演变需要持续开发有效的抑制剂.
研究的目的:
- 使用计算机辅助药物设计 (CADD) 识别SARS-CoV-2尖端蛋白的新型抑制剂.
- 验证已识别的化合物对SARS-CoV-2及其变体的抗病毒活性.
主要方法:
- 利用CADD对来自NCI数据库的26万多种化合物进行选,以对抗SARS-CoV-2尖端蛋白受体结合域 (RBD).
- 使用SARS-CoV-2伪病毒进行基于细胞的测试,以评估抗病毒疗效.
- 最初的化合物的生成和测试衍生物.
主要成果:
- 确定了具有显著SARS-CoV-2抗病毒活性的初始化合物 (C2,C8,C10) (EC50值在6.7至8.8μM之间).
- 优化的化合物C8.2证明了增强的疗效 (EC50 = 5.9 μM).
- 化合物C8.2也显示出对Omicron变体 (EC50 = 9.3μM) 的抑制活性.
结论:
- CADD是发现SARS-CoV-2尖端蛋白抑制剂的有效策略.
- 化合物C8.2代表了开发针对SARS-CoV-2及其变种的治疗方法的有希望的领先地位.
- 准尖蛋白RBD为抗病毒药物开发提供了一种可行的方法.
相关概念视频
Single Nucleotide Polymorphisms-SNPs
A single nucleotide polymorphism or SNP is a single nucleotide variation at a specific genomic position in a large population. It is the most prevalent type of sequence variation found in the human genome. Point mutations that occur in more than 1% of the population qualify as SNPs. These are present once every 1000 nucleotides on an average in the human genome. Replacement of a purine with another purine (A/G) or a pyrimidine with another pyrimidine (C/T) is known as a transition. In contrast,...
Coronavirus
Coronaviruses, including the severe acute respiratory syndrome coronavirus (SARS-CoV), are enveloped viruses characterized by their single-stranded, positive-sense RNA genome and helical nucleocapsid structure. The hallmark of these viruses is their club-shaped spike (S) glycoproteins that protrude from the viral envelope, facilitating attachment to host cells. Typically, coronaviruses infect the upper respiratory tract, often causing mild or asymptomatic disease. However, certain strains like...
Inhibitors of Viral Protein Synthesis
Protein synthesis is indispensable for viral replication, as viruses lack the cellular machinery required for this process and must hijack the host's translational apparatus. In response, host cells deploy a critical innate immune defense involving interferons, specialized cytokines that play a central role in inhibiting viral propagation.Upon viral detection, infected cells release interferons that bind to receptors on adjacent uninfected cells, activating the JAK-STAT signaling pathway and...
Inhibitors Of Virion Release
Viral replication and dissemination rely on efficient mechanisms for host cell entry, genome replication, assembly, and release. Influenza viruses, such as types A and B, are negative-sense single-stranded RNA viruses with a segmented genome, that depend on two critical surface glycoproteins to carry out these processes: hemagglutinin (HA) and neuraminidase (NA). HA initiates infection by binding to sialic acid residues on the surface of host epithelial cells, facilitating receptor-mediated...


