DESIGN, SYNTHESIS AND STRUCTURE OF NON-MACROCYCLIC INHIBITORS OF FKBP12, THE MAJOR BINDING-PROTEIN FOR THE IMMUNOSUPPRESSANT FK506

We have synthesized a series of non-macrocyclic ligands to FKBP12 that are comparable in binding potency and peptidyl prolyl isomerase (PPIa se) inhibition to FK506 itself. We have also solved the structure of o ne of these ligands in complex with FKBP12, and have compared that str ucture to the FK506-FKBP12 complex. Consistent with the observed inhib itory equipotency of these compounds, we observe a strong similarity i n the conformation of the two Ligands in the region of the protein tha t mediates PPIase activity. Our compounds, however, are not immunosupp ressive. In the FKBP12-FK506 complex, a significant portion of the FK5 06 ligand, its 'effector domain', projects beyond the envelope of the binding protein in a manner that is suggestive of a potential interact ion with a second protein, the calcium-dependent phosphatase, calcineu rin, whose inhibition by the FKBP12-FK506 complex interrupts the T-cel l activation events leading to immunosuppression. In contrast, our com pounds bind within the surface envelope of FKBP12, and induce signific ant changes in the structure of the FKBP12 protein which may also affe ct calcineurin binding indirectly.