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 PROTAC approach” in Journal of the American Chemical Society, which reported a kind of polypeptide self-assembled Split-and-Mix PROTAC (SM-PROTAC) 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, PROTAC), 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 PROTAC 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 PROTAC technology as an example, the author validates the concept of split-assembly nano-platform and puts forward the design concept of SM-PROTAC nanospheres formed by peptide self-assembly. SM-PROTAC differs from conventional small molecule PROTAC 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-PROTACs 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-PROTAC can eliminate the laborious and time-consuming process of screening linkers for conventional small molecule PROTAC.
The authors verified their degradation activity, degradation mechanism, and adjustability in ER α and CDK4/6 targets, and verified the versatility of SM-PROTAC platform on several targets such as AR, EGFR, MEK1/2, BRD2/4, and BCR-ABL. As a PROTAC platform, SM-PROTAC aims to provide new solutions to some challenges encountered in PROTAC 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 PROTAC, and rationalizing the design of traditional PROTAC.
This study successfully developed a new drug research and development platform, SM-PROTAC, by applying split-assembly nano-platform and peptide self-assembly technology to PROTAC technology. SM-PROTAC 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-PROTAC has a significant impact on drug research and development and offers a novel approach to drug research and development.