含有氨基醇5'-酸酶 (SHIP) 的SH2域的氨基醇和氨基酸抑制剂
Angela M Pacherille1, Dennis R Viernes1, Chiara Pedicone2
1Department of Chemistry, Syracuse University, 111 College Place, Syracuse, NY, 13244, USA.
ChemMedChem
|January 22, 2025
概括
研究人员开发了更多水溶性氨基类抑制剂,向含有SH2的内醇酸酶 (SHIP) 酶. 这些新型化合物抑制SHIP1和SHIP2,为研究这些酶在阿尔茨海默氏症和癌症等疾病中提供了潜力.
科学领域:
- 生物化学 生物化学
- 药用化学 医学化学
- 药理学 药理学是指药理学的学科.
背景情况:
- 含SH2的内醇酸酶 (SHIP) 是阿尔茨海默氏症,移植与宿主疾病,肥胖和癌症的治疗点.
- 氨基类固醇SHIP抑制剂,如3α-aminocholestane (3AC),正在研究中.
- 提高SHIP抑制剂的水溶性对于其治疗开发至关重要.
研究的目的:
- 合成和评估具有增强水溶性3AC的新型氨类类似物.
- 研究这些类似物对SHIP1和SHIP2的抑制活性.
- 为了阐明SHIP活动地点内的抑制和结合相互作用的机制.
主要方法:
- 氨类固醇类似物的化学合成,对胆固醇骨进行修改.
- 酶抑制试验以确定对SHIP1和SHIP2的活性.
- 酶动力学研究以描述抑制的模式.
- 分子建模以可视化SHIP1活性部位内的抑制剂结合.
主要成果:
- 删除C17基组的类似物表现出更好的水溶性.
- 这些修改后的化合物显示出抑制SHIP1和SHIP2 (泛SHIP1/2抑制).
- 酶动力学表明竞争性抑制,与基质部位附近的结合.
- 基于结构-活动关系,为SHIP1提出了一个具有约束力的模型.
结论:
- 新型水溶性氨类泛SHIP1/2抑制剂已经开发出来.
- 这些化合物为未来研究SHIP酶功能和治疗应用提供了宝贵的工具.
- 这些发现有助于理解SHIP针对各种疾病的药物设计.
相关概念视频
Phosphoinositides and PIPs
8.4K
Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
8.4K
The JAK-STAT Signaling Pathway
8.6K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
8.6K
Indirect-Acting Cholinergic Agonists: Mechanism of Action
1.5K
Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex,...
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex,...
1.5K
IP3/DAG Signaling Pathway
11.8K
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
11.8K
Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
515
Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
515
Inhibition of Cdk Activity
4.6K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.6K


