Rapamycin and its various analogs have been used extensively to induce dimerization of FKBP and FRB domains, as well as proteins fused to them. This has been used to control a wide range of biological processes, including activation of split-proteins, intracellular protein translocation, and protein stabilization. Small molecule induced dimerization of proteins, while an important tool in chemical biology, has previously been limited in its irreversible behavior. Gaining the ability to turn the FKBP-rapamycin-FRB ternary complex back off is significant to the study of the reversible nature of biological processes. In this work, two methods were developed toward this goal – photoswitchable rapamycin analogs were used with the aim of inducing and breaking the ternary complex in response to a configurational change, while ROS-generating rapamycin analogs were used to oxidize and deactivate the ternary complex with singlet oxygen upon irradiation. Though photoswitching did not provide the necessary structural changes required to break a rapamycin-induced ternary complex, we showed targeted protein oxidation via optically triggered singlet oxygen generation can be used as an off-switch for rapamycin-induced protein interactions.

Rapamycin-based optical on- and off-switches of protein function

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.