Recently, the Li Zigang and Yin Feng research group of Shenzhen Graduate School of Peking University published a research paper entitled “Targeted biomolecule regulation platform: a Split-and-Mix Protein Degrader approach” in Journal of the American Chemical Society, which reported a kind of polypeptide self-assembled Split-and-Mix Protein Degrader (SM-Protein Degrader) and achieved obvious degradation effect on ER α, EGFR, MEK1/2, BRD2/4, CDK4/6, AR, BCR-ABL and other targets.
Targeted protein degradation technology (Proteolysis targeting chimeras, Protein Degrader), as a new protein degradation technology, has unmatched potential advantages over small molecule inhibitors, such as targeting non-proprietary drugs and overcoming drug resistance, and is undergoing rapid development. However, the underlying patented technology of Protein Degrader is primarily mastered by developed countries.
Based on the observation that different biomolecules can perform their biological functions after recognizing each other, the author assumes that the Split-and-Mix nano-platform can be used as a self-regulating platform, which can easily screen the ligand molecules put into assembly and adjust the proportion of ligands during assembly. in the assembly process. Using Protein Degrader technology as an example, the author validates the concept of split-assembly nano-platform and puts forward the design concept of SM-Protein Degrader nanospheres formed by peptide self-assembly. SM-Protein Degrader differs from conventional small molecule Protein Degrader in that it divides the ligand small molecule targeting E3 ubiquitin ligase and the ligand small molecule of target protein into two modules and then dissolves them and reassembles them. Finally, the SM-Protein Degraders with diameters ranging from 50 to 300 nm were assembled. The surface of such nanospheres contains multiple small molecules targeting E3 ligands and multiple small ligand molecules targeting the protein of interest. Due to the proximity effect, the E3 ubiquitin ligase labels the target protein that is then recognized and degraded by the proteasome. SM-Protein Degrader can eliminate the laborious and time-consuming process of screening linkers for conventional small molecule Protein Degrader.
The authors verified their degradation activity, degradation mechanism, and adjustability in ER α and CDK4/6 targets, and verified the versatility of SM-Protein Degrader platform on several targets such as AR, EGFR, MEK1/2, BRD2/4, and BCR-ABL. As a Protein Degrader platform, SM-Protein Degrader aims to provide new solutions to some challenges encountered in Protein Degrader drug development, such as rapid and effective screening of target protein ligands, rapid screening of E3 ubiquitin ligase ligands, expanding the scope of use of E3 ubiquitin ligases in Protein Degrader, and rationalizing the design of traditional Protein Degrader.
This study successfully developed a new drug research and development platform, SM-Protein Degrader, by applying split-assembly nano-platform and peptide self-assembly technology to Protein Degrader technology. SM-Protein Degrader has the benefits of high efficiency, reliability, and time savings, and has a wide range of potential applications in the field of drug research and development. The Split-and-Mix nano-platform concept can be applied to other degradation agent systems, such as LYTAC, AUTAC, and RIBOTAC, to create SM-LYTAC, SM-AUTAC, SM-RIBOTAC, etc. The successful development of SM-Protein Degrader has a significant impact on drug research and development and offers a novel approach to drug research and development.