针对目标蛋白质降解的下一步.
Mackenzie W Krone1, Craig M Crews2
1Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
Cell chemical biology
|November 5, 2024
概括
向蛋白质降解 (TPD) 是一个有前途的治疗策略,新的分子降解剂接近临床批准. 为了扩大其医疗应用,需要在TPD平台,合成和复杂优化方面取得进一步的进步.
科学领域:
- 生物化学 生物化学
- 药理学 药理学是指药理学的学科.
- 药用化学 医学化学
背景情况:
- 在过去的二十年中,有针对性的蛋白质降解 (TPD) 已成为一种强大的治疗策略.
- 调节生物分子邻近性的化学方法比传统的蛋白质抑制具有优势,可以准以前无法治疗的与疾病相关的蛋白质.
研究的目的:
- 突出TPD领域未来增长的关键领域.
- 确定开发下一代分子降解剂的战略.
- 要强调TPD在扩大治疗应用中的潜力.
主要方法:
- 审查和综合TPD当前的进展.
- 确定需要进一步研究和开发的关键领域.
- 专注于时空精度,合成吞吐量和复杂的合作性.
主要成果:
- 对于针对无法药物治疗的蛋白质,TPD提供了药理上的优势.
- 临床前成功和现有的临床疗法证明了TPD的潜力.
- 已经确定了扩大TPD工具箱的三个优先领域.
结论:
- 在TPD平台,合成和诱导蛋白质复合体优化的持续创新至关重要.
- 这些领域的进展将扩大近距离诱导药理学的治疗应用.
- 医学中TPD的未来是有希望的,具有显著临床影响的潜力.
相关概念视频
The Proteasome
8.5K
Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
8.5K
Regulated Protein Degradation
7.2K
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
7.2K
The Proteasome Structure
708
The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
The proteasome is an...
708
Export of Misfolded Proteins out of the ER
3.5K
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
3.5K
Proteins: From Genes to Degradation
12.1K
Within a biological system, the DNA encodes the RNA, and the nucleotide sequence in the RNA further defines the amino acid sequence in the protein. This is referred to as “The Central Dogma of Molecular Biology” - a term coined by Francis Crick. Central dogma is a firm principle in biology that defines the flow of genetic information within any life form. The two fundamental steps in central dogma are - transcription and translation.
Transcription is the synthesis of RNA...
Transcription is the synthesis of RNA...
12.1K
mRNA Stability and Gene Expression
5.5K
The structure and stability of mRNA molecules regulates gene expression, as mRNAs are a key step in the pathway from gene to protein. In eukaryotes, the half-life of mRNA varies from a few minutes up to several days. mRNA stability is essential in growth and development. The absence of the proteins regulating its stability, such as tristetraprolin in mice, can cause systemic issues, including bone marrow overgrowth, inflammation, and autoimmunity.
Cis-acting Elements involved in mRNA stability
Cis-acting Elements involved in mRNA stability
5.5K


