血管内皮细胞生长因子的迪默联体:优化链接器长度以获得高亲和力和抗血管性活性
Xiaoqing Ye1, Jean-François Gaucher2, Haofeng Hu1,3
1CiTCoM, UMR CNRS 8038, U1268 INSERM, Université Paris Cité, Faculté de Santé, UFR de Pharmacie, 4 av. de l'Observatoire, 75006 Paris, France.
Journal of medicinal chemistry
|July 6, 2023
概括
研究人员开发了较小的,高亲和度的二极体,针对血管内皮生长因子A (VEGF). 这一策略显著提高了结合亲和力,为新的癌症和眼睛疾病治疗提供了潜力.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 针对血管内皮生长因子A (VEGF) 的宏分子配体在临床上用于抑制癌症和眼部疾病的病态血管生成.
- 开发具有高亲和力的较小配体对于改善治疗应用至关重要.
研究的目的:
- 设计和合成针对VEGF同位体同位体对称结合部位的同位体.
- 通过使用灵活的聚乙烯糖醇 (PEG) 连接器来增强连接体亲和力,通过激情效应来增强连接体亲和力.
- 评估这些新型二维联结体的治疗潜力.
主要方法:
- 合成了11个具有不同PEG链接长度的同位素.
- 使用大小排除色谱测定结合模式.
- 通过异热定位热量计测量热力学结合参数的测量,与bevacizumab相比.
- 链接长度效应与理论模型的相关性.
- 在使用人类静脉内皮细胞 (HUVECs) 的基于细胞的试验中验证二聚体活性.
主要成果:
- 与单体对照相比,在二元D6中最优的PEG链接长度导致结合亲和力提高了40倍.
- 获得了为优化的二次体的单位纳米分离常数 (Kd).
- 在基于细胞的测试中证明了二分化策略的有效性.
结论:
- 二聚化是一种有效的策略,可以为VEGF.产生更小,高亲和度的配体.
- 优化的D6二聚体显示出在血管生成相关疾病中治疗应用的巨大潜力.
- 这种方法为较大的宏分子抑制剂提供了一个有希望的替代方案.
相关概念视频
01:24Regulation of Angiogenesis and Blood Supply
2.6K
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
2.6K
00:49Ligand Binding and Linkage
4.8K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.8K
02:40Ligand Binding Sites
12.9K
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
12.9K