Chemical protein degradation methods like protein degradation targeted chimera (Protein Degrader) allow for the simultaneous targeting of E3 ligase and disease-related proteins, with the latter then being degraded by the body’s own ubiquitin-protease system. Since the Crew research group proposed the idea of Protein Degrader in 2001, other research groups have dedicated significant resources to developing Protein Degrader further. Systematic research into Protein Degrader technology has revealed that it often degrades proteins in cells and tissues without being selective, which can result in off-target damage. The researchers proposed Pro-Protein Degrader as a solution to this issue, which seeks to conditionally regulate the targeted degradation activity of Protein Degrader molecules via various response modes in order to enhance Protein Degrader’s spatial and temporal resolution and reduce the possibility of Protein Degrader’s toxicity to normal cells.
Photoresponsive Pro-Protein Degrader
Photocaged Protein Degraders
Photocage protection groups were introduced into E3 ligase ligands, target protein ligands, and connectors in active Protein Degrader molecules to block the targeted degradation of Protein Degrader molecules with different molecular mechanisms.
In 2019, the Pan Zhengying research group at Peking University synthesized the first example of photodetached Protein Degrader (pc-Protein Degrader) by including the photocontrolled group DMNB into the Protein Degrader molecule (dBET1) that destroys BRD4 protein. By UV irradiation, Pc-Protein Degrader enhanced the spatial and temporal resolution of Protein Degrader, indicating that it was an inactive molecule prior to illumination, but was able to successfully degrade the target protein in both cells and zebrafish after illumination. Simultaneously, other outstanding research groups have investigated the synthesis and design of various light cage protection groups on Protein Degrader molecules, increasing the applicability of the light cage technique to Protein Degrader molecular design.
Photoswitchable Protein Degraders
Azobenzene groups are a family of optically switchable compounds whose conformational changes are governed by two wavelengths. In Protein Degrader molecular design, the inclusion of azobenzene groups into the connectors can reversibly regulate the degradation activity of Protein Degrader molecules and forecast the association between conformational changes and changes in Protein Degrader molecules’ degradation activity.
In 2019, the Erick M. Carreira team of the Zurich Institute of Technology and the Craig M. Crews team of Yale University reported on the Protein Degrader molecular design of photoregulation. Under the influence of dual wavelength light, the photoProtein Degrader can flip between the active state of trans conformation and the inactive state of cis conformation, enabling the spatiotemporal control of targeted degradation of BRD4. Simultaneously, other outstanding research groups have investigated the utilization of azobenzene groups in Protein Degrader molecular design.
Despite the fact that photoresponsive Pro-Protein Degrader molecules can enhance the miss toxicity of Protein Degrader under photocontrol circumstances, there is still a long way to go before they can be employed in clinical treatment due to their low tissue penetration and potential phototoxicity.