Chemical protein degradation methods like protein degradation targeted chimera (PROTAC) 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 PROTAC in 2001, other research groups have dedicated significant resources to developing PROTAC further. Systematic research into PROTAC 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-PROTAC as a solution to this issue, which seeks to conditionally regulate the targeted degradation activity of PROTAC molecules via various response modes in order to enhance PROTAC’s spatial and temporal resolution and reduce the possibility of PROTAC’s toxicity to normal cells.
Photoresponsive Pro-PROTAC
Photocaged PROTACs
Photocage protection groups were introduced into E3 ligase ligands, target protein ligands, and connectors in active PROTAC molecules to block the targeted degradation of PROTAC molecules with different molecular mechanisms.
In 2019, the Pan Zhengying research group at Peking University synthesized the first example of photodetached PROTAC (pc-PROTAC) by including the photocontrolled group DMNB into the PROTAC molecule (dBET1) that destroys BRD4 protein. By UV irradiation, Pc-PROTAC enhanced the spatial and temporal resolution of PROTAC, 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 PROTAC molecules, increasing the applicability of the light cage technique to PROTAC molecular design.
Photoswitchable PROTACs
Azobenzene groups are a family of optically switchable compounds whose conformational changes are governed by two wavelengths. In PROTAC molecular design, the inclusion of azobenzene groups into the connectors can reversibly regulate the degradation activity of PROTAC molecules and forecast the association between conformational changes and changes in PROTAC 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 PROTAC molecular design of photoregulation. Under the influence of dual wavelength light, the photoPROTAC 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 PROTAC molecular design.
Despite the fact that photoresponsive Pro-PROTAC molecules can enhance the miss toxicity of PROTAC 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.