Probing immunosuppressant action with a nonnatural immunophilin ligand.

Science
Authors
Keywords
Abstract

The immunosuppressants FK506 and rapamycin bind to the same immunophilin, FK506 binding protein (FKBP), and inhibit distinct signal transduction pathways in T lymphocytes. A nonnatural immunophilin ligand, 506BD, which contains only the common structural elements of FK506 and rapamycin, was synthesized and found to be a high-affinity ligand of FKBP and a potent inhibitor of FKBP rotamase activity. Whereas 506BD does not interfere with T cell activation, it does block the immunosuppressive effects of both FK506 and rapamycin. Thus, the common immunophilin binding element of these immunosuppressants, which is responsible for rotamase inhibition, is fused to different effector elements, resulting in the inhibition of different signaling pathways. Inhibition of rotamase activity is an insufficient requirement for mediating these effects.

Year of Publication
1990
Journal
Science
Volume
250
Issue
4980
Pages
556-9
Date Published
1990 Oct 26
ISSN
0036-8075
PubMed ID
1700475
Links
Grant list
GM-38627 / GM / NIGMS NIH HHS / United States
P01-CA-39542 / CA / NCI NIH HHS / United States