迪苏尔菲拉姆通过对其基质进入部位的结合来抑制冠状病毒主要蛋白酶
Ying Kuan1, Hsu-Feng Chu2, Pang-Hung Hsu3
1Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan.
International journal of biological macromolecules
|July 18, 2024
概括
酒精治疗药物迪苏尔菲拉姆显示对冠状病毒 (CoV) 主蛋白酶 (Mpro) 的广泛抑制. 它的目标是Mpro.
科学领域:
- 病毒学 病毒学
- 药物发现 药物发现 药物发现
- 生物化学 生化学
背景情况:
- 冠状病毒 (CoV) 是致病性RNA病毒,导致严重的呼吸系统疾病和经济损失.
- 保存的主要蛋白酶 (Mpro) 或3CLpro是对抗CoV的抗病毒疗法的关键标.
- Mpro对于病毒复制至关重要,它调解病毒多蛋白质的蛋白质分解裂变.
研究的目的:
- 为了研究迪苏尔菲拉姆作为Cov Mpro.的宽谱抑制剂的潜力.
- 阐明迪苏尔菲拉姆与 CoV Mpro.相互作用并抑制的机制.
主要方法:
- 分析超离心和循环二极化,以评估Mpro的稳定性和二极化.
- 质谱和结构对齐以确定Mpro.上迪苏尔菲拉姆的结合部位.
- 分子对接模拟,以预测二硫对基质结合的干扰.
- 位点定向突变发生 (Cys44) 来确认已识别的残留物的作用.
主要成果:
- 迪苏尔菲拉姆通过阻断二分化和降低热稳定性来抑制SARS,SARS-2和PEDV Mpro.
- 迪苏尔菲拉姆促进了MERS Mpro的二分化和稳定性,表明了多种效应.
- 迪苏尔菲拉姆向Mpro基质入口处的Cys44残留物,位于催化部位附近.
- 迪苏尔菲拉姆结合干扰了基质进入催化中心,由Cys44突变研究证实.
结论:
- 迪苏尔菲拉姆对各种CovMpro酶表现出广泛的抑制活性.
- 迪苏尔菲拉姆的机制涉及向Cys44,影响Mpro二分化,稳定性和基质结合.
- 迪苏尔菲拉姆是治疗各种冠状病毒感染的有希望的治疗候选药物.
相关概念视频
01:30Enzyme Inhibition
Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
01:26Pharmacokinetics: Drug–Food and Drug–Viral Interactions
A drug interaction occurs when the concurrent use of another drug, food, or an external substance alters the pharmacological activity of a drug. This interaction can modify the action of the original drug, affecting its effectiveness and safety.Drug–food interactions are significant as they impact drug absorption, metabolism, and excretion. For example, grapefruit juice is a well-known disruptor of drug metabolism. It inhibits the cytochrome P450 3A4 enzyme, crucial for the metabolism of many...
01:29Subviral Agents
Subviral agents are infectious entities that resemble viruses but lack one or more viral components, such as a capsid or essential replication machinery. These agents include viroids, prions, and satellites, each possessing distinct structural and functional characteristics that influence their mode of infection and replication.Viroids are the simplest subviral agents, consisting of circular, single-stranded RNA molecules without a protein coat. They exclusively infect plants, relying entirely...
01:25Inhibitors of Bacterial Protein Synthesis
Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...
01:28Inhibitors of Bacterial DNA Synthesis
Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These antibiotics are selectively...
01:30Inhibitors 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...