直接和全蛋白体共价抑制剂位识别的化学蛋白质策略
Christopher M Browne1,2, Baishan Jiang1,2, Scott B Ficarro1,2,3
1Department of Cancer Biology , Dana-Farber Cancer Institute , Boston , Massachusetts 02215 , United States.
Journal of the American Chemical Society
|December 7, 2018
概括
一种新的化学蛋白质组方法,CITE-ID,精确地绘制了蛋白质上的共价药结合点. 这种方法确定了药物开发的新点,包括研究不足的PKN3激酶,从而产生了一种新型选择性抑制剂.
科学领域:
- 蛋白质组学
- 化学生物学
- 药物发现
背景情况:
- 协价药物具有治疗优势,但由于异于目标氨酸的修饰而面临毒性风险.
- 目前的方法缺乏直接的氨基酸水平定量对蛋白质组的共价抑制剂的结合.
研究的目的:
- 为准确地绘制共价药物相互作用的新型化学蛋白质方法CITE-ID.
- 描述共价抑制剂的全蛋白选择性,并确定新的药物标.
主要方法:
- 开发CITE-Id,一种使用共价抑制剂作为缩试剂的化学蛋白质平台.
- 在蛋白质组中对剂量依赖的氨酸-醇修饰的定量分析.
- 用CITE-Id研究不可逆转的CDK抑制剂THZ1.
主要成果:
- 通过共价抑制剂,CITE-Id可直接量化剂量依赖的氨酸修饰.
- 对THZ1的分析揭示了意想不到的酶标,包括PKN3 (C840) 上的一种新囊素.
- 这导致了PKN3的选择性共价抑制剂JZ128的开发,并确定了其基质.
结论:
- CITe-Id是一种强大的工具,用于表征共价抑制剂的选择性和识别新型可用药的囊蛋白.
- 该方法为基于结构的药物设计提供了信息,并加速了向共价疗法的开发.
- 这项工作为PKN3生物学及其作为药物点的潜力提供了新的见解.
相关概念视频
Covalent Bonds
162.2K
Overview
162.2K
Covalent Bonds
10.9K
Overview
When two atoms share electrons to complete their valence shells, they create a covalent bond. An atom's electronegativity—the force with which shared electrons are pulled towards an atom—determines how the electrons are shared. Molecules formed with covalent bonds can be either polar or nonpolar. Atoms with similar electronegativities form nonpolar covalent bonds; the electrons are shared equally. Atoms with different electronegativities share electrons unequally,...
When two atoms share electrons to complete their valence shells, they create a covalent bond. An atom's electronegativity—the force with which shared electrons are pulled towards an atom—determines how the electrons are shared. Molecules formed with covalent bonds can be either polar or nonpolar. Atoms with similar electronegativities form nonpolar covalent bonds; the electrons are shared equally. Atoms with different electronegativities share electrons unequally,...
10.9K
Network Covalent Solids
16.2K
Network covalent solids contain a three-dimensional network of covalently bonded atoms as found in the crystal structures of nonmetals like diamond, graphite, silicon, and some covalent compounds, such as silicon dioxide (sand) and silicon carbide (carborundum, the abrasive on sandpaper). Many minerals have networks of covalent bonds.
To break or to melt a covalent network solid, covalent bonds must be broken. Because covalent bonds are relatively strong, covalent network solids are typically...
To break or to melt a covalent network solid, covalent bonds must be broken. Because covalent bonds are relatively strong, covalent network solids are typically...
16.2K
Antihypertensive Drugs: Direct Renin Inhibitors
1.5K
The renin-angiotensin-aldosterone system (RAAS) is an intricate physiological pathway involving numerous enzymes and hormones, including renin, angiotensin-converting enzyme (ACE), angiotensin I and II, and aldosterone. Imbalances within this system increase the production of angiotensin II and aldosterone. Increased angiotensin II levels promote vasoconstriction and blood pressure elevation. Concurrently, higher aldosterone levels stimulate sodium and water reabsorption in the kidneys,...
1.5K
Covalent Bonding and Lewis Structures
61.3K
Compared to ionic bonds, which results from the transfer of electrons between metallic and nonmetallic atoms, covalent bonds result from the mutual attraction of atoms for a “shared” pair of electrons.
61.3K
Covalently Linked Protein Regulators
9.6K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
9.6K


