模仿ATP的向prolyl-tRNA合成酶是抗疟疾药物开发的新途径
Siddhartha Mishra1,2,3, Nipun Malhotra1, Benoît Laleu4
1Molecular Medicine - Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi 110067, India.
iScience
|August 6, 2024
概括
研究人员开发了五种针对prolyl-tRNA合成酶 (PRS) 的新化合物,这种酶对疟疾寄生虫的生存至关重要. 化合物L35表现出显著的热稳定性和强大的抑制作用,为新的抗疟疾药物开发提供了有前途的途径.
科学领域:
- 生物化学 生物化学
- 药用化学 医学化学
- 寄生虫学的寄生虫学
背景情况:
- 普罗-tRNA合成酶 (PRS) 对于蛋白质合成至关重要,也是针对疟疾的验证药物标.
- 开发针对Plasmodium falciparum PRS的新型抑制剂对于对抗疟疾至关重要.
研究的目的:
- 设计和描述针对Plasmodium falciparum prolyl-tRNA合成酶 (PfPRS) 的新型ATP模拟剂.
- 评估这些化合物对疟疾寄生虫的抑制效能,选择性和结构基础.
主要方法:
- 合成和描述五种ATP模拟剂 (L95,L96,L97,L35,L36) 的情况.
- 测试热稳定性,酶抑制和细胞活性,以对抗无性血阶段 (ABS) 菌.
- 用抑制剂和L-proline复合的PfPRS的宏分子结构确定.
主要成果:
- 化合物L95,L96,L97,L35和L36与L-proline一起显示了增强的热稳定性.
- 四种化合物表现出对PfPRS的纳米分子抑制作用.
- 对于寄生虫来说,L35表现出高的热稳定性,强大的抑制 (∼1.6 nM) 和显著的选择性 (∼100倍EC50).
- 结构分析揭示了化合物结合模式,并突出了PfPRS的催化位点可性,其中涉及Arg401.1的特定相互作用.
结论:
- 开发的ATP模仿剂,特别是L35,显示出作为抗疟疾药物候选者的重大前景.
- 了解抑制的结构基础为针对PfPRS的合理药物设计提供了基础.
- 用特定和选择性抑制剂向PfPRS是开发疟疾药物的可行策略.
相关概念视频
01:48ATP Synthase: Mechanism
14.3K
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
14.3K
01:18ATP Synthase: Structure
12.1K
ATP synthase or ATPase is among the most conserved proteins found in bacteria, mammals, and plants. This enzyme can catalyze a forward reaction in response to the electrochemical gradient, producing ATP from ADP and inorganic phosphate. ATP synthase can also work in a reverse direction by hydrolyzing ATP and generating an electrochemical gradient. Different forms of ATP synthases have evolved special features to meet the specific demands of the cell. Based on their specific feature, ATP...
12.1K
01:30The Electron Transport Chain
16.4K
The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...
16.4K
01:26Targets for Drug Action: Overview
6.1K
Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
6.1K