* Please be kindly noted that our services and products can only be used for research to organizations or companies and not intended for any clinical or individuals.
BOC Sciences is a leading CRO providing innovative drug discovery services. In recent years, we have focused on drug discovery based on the ubiquitin-proteasome system (UPS), providing research tools for small-molecule targeted drugs to better assist our clients and accelerate their new drug development processes. It is worth mentioning that the PROTAC technology uses the cell's own UPS to induce the degradation of target proteins, and our services cover all aspects of PROTAC® development.
The ubiquitin-proteasome system (UPS) is the major pathway for the degradation of intracellular proteins in eukaryotic cells. Proteins that are tagged with multi-ubiquitins are recognized and degraded by the proteasome. Nobel Prize in Chemistry 2004 was awarded jointly to three scientists for discovering ubiquitin-mediated protein degradation.
Protein ubiquitination is mediated by a series of ubiquitinating enzymes, which are ubiquitin-activating enzyme E1, ubiquitin conjugase E2, and ubiquitin ligase E3. First, ubiquitin is activated by hydrolysis of ATP to form a thioester bond between the carboxyl terminus of ubiquitin and the active site cysteine of E1. Then, ubiquitin is transferred to E2 and subsequently attached to the active group (e.g., lysine residue, N-terminal amino group) by E3 in the substrate. Additional ubiquitin molecules bind to the first ubiquitin molecule, forming a poly-ubiquitinated target protein recognized by the proteasome and leading to substrate degradation.
Fig 1. The ubiquitin-proteasome system (Zhang, 2020)
Scientists have designed to use the naturally occurring intracellular protein degradation systems to degrade disease-associated proteins for disease treatment. The UPS-based targeted protein degradation technology consists mainly of PROTAC (proteolysis-targeting chimera) and molecular glue. The characteristics of PROTACs and molecular glues are listed below:
|Mechanism||Binds target and E3||Binds E3 or target protein to induce PPI|
|Target protein||Predictable||To be determined|
|Discovery strategy||Rational design||Historically serendipitous discovery|
|Linker||With linker||Without linker|
|Rule of five||Beyond||Typically with|
|Binding pocket in the target protein||Required||Nonessential|
Table 1. Characteristics of PROTAC and molecular glue (Dong, 2021)
* PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.
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