* 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 provides professional peptide-based PROTAC development services, including molecular structure design, validation, and optimization, to help you design your drug efficiently and rationally. We also have an experienced synthesis team to provide you with fast, cost-effective, and high-quality synthesis of the final peptide-based PROTAC molecules.
Fig.1 Development of peptide-based PROTACs. (Dai et al., 2020)
PROTAC is essentially a bifunctional small molecule that targets the target protein on one hand and recruits ubiquitin ligases (E3) on the other hand to achieve targeted degradation of the target protein. The design of PROTACs can be extended to assemble a variety of small molecule ligands including peptides in drug development. Based on the peptide used in the development of PROTAC, the design of PROTAC needs to consider the structure and properties of the peptide. First, key structural domains or functional regions of the peptide need to be identified that can bind to target and trigger ubiquitination degradation. Then, the corresponding linkers are designed and optimized to have high affinity and selectivity to bind to the target and modulate its activity.
In the development of peptide-based PROTACs, rational design is required to construct the PROTAC molecules. Subsequently, the development of peptide-based PROTAC is completed through continuous experimental validation as well as structural optimization to achieve the desired goal.
PROTAC design requires consideration of the parts that make up the PROTAC.
Target protein-ligand design requires selecting the target protein first, then analyzing the structure and function of the target protein to determine the key structural domains or functional regions and designing the corresponding peptide ligands.
CRBN and VHL are the most commonly used ligands. In principle, we need to determine the abundance of E3 ligase in the target cells by using the E3 ligase kit to select the best E3 ligase ligand.
PEG chains are often chosen as the linker molecule for the initial PROTAC design, as they are flexible enough to adjust the molecule to the appropriate binding angle.
The peptide and E3 ligase ligand are linked together by linker molecules to form a peptide-based PROTAC, which can be realized by chemical synthesis methods, such as click chemistry and nucleophilic substitution.
Although a PROTAC molecule can be initially constructed after the above rational design, it is not necessarily active and requires experimental verification and design summarization. When analyzing the reasons for structure optimization, it is also necessary to consider the molecules selected in each step of the design, the reasonableness of the attachment sites, and the membrane permeability of the overall PROTAC.
Functional evaluation of the synthesized peptide-PROTAC is performed, including the study of ubiquitination degradation effect, biological activity and cytotoxicity of the target protein. Based on the evaluation results, necessary optimization and improvement are carried out to enhance the effectiveness and specificity of the peptide-PROTAC.
* PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.
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