Related Experiment Videos
Design and synthesis of a rapamycin-based high affinity binding FKBP12 ligand
T K Chakraborty1, H P Weber, K C Nicolaou
1Organic Division III, Indian Institute of Chemical Technology, Hyderabad, India.
Background:
The immunosuppressants rapamycin, ascomycin, FK506, and cyclosporin act by binding to a class of cytosolic proteins, the immunophilins. In the case of FK506, ascomycin and cyclosporin, the target of the immunophilin-immunosuppressant complex is calcineurin; in the case of rapamycin, the target is FRAP (TOR/RAFT1). Rapamycin, ascomycin and FK506 have a common domain responsible for binding to FKBP12, their cellular receptor, and different effector domains that determine the target of the complex. Both domains are necessary for signal transduction and biological activity.
Results:
A hybrid molecule containing the rapamycin-FK506-ascomycin binding domain and a peptide tether has been designed, synthesized and biologically evaluated. The designed compound binds to FKBP12 with high affinity but has no biological activity, as expected from its lack of an effector domain.
Conclusions:
The designed rapamycin-based FKBP12 ligand exhibits powerful binding properties but, unlike rapamycin, shows no activity in IL-6 dependent B-cell proliferation and, in contrast to FK506, shows no activity in the IL-2 reporter assay. The modular nature of this designed molecule should make it possible to generate a series of compounds with effector domains for targeting either calcineurin or FRAP (TOR/RAFT1) or both, as potential biological tools and immunosuppressive agents.