X-RAY STRUCTURE OF THE
COMPLEX FKBP12/RAD AT 1.8A RESOLUTION
(RAD IS A NEW IMMUNOSUPPRESSIVE
DERIVATIVE OF RAPAMYCIN FROM NOVARTIS PHARMA AG)
Jörg Kallen1, Richard Sedrani2 , Sylvain Cottens2, Walter Schuler2
1Novartis Pharma AG, Dept.
of Core Technology, CH-4002, Basel, Switzerland
2Novartis Pharma AG, Dept. of
Transplantation, CH-4002, Basel, Switzerland
Keywords: FKBP12, rapamycin,
immunosuppression
The immunosuppressive macrolide rapamycin (RAP) has attracted interest in recent years because of its immunosuppressive properties, but this complex natural product exhibits unfavourable physicochemical properties. We therefore embarked on a program aimed at overcoming these difficulties by chemical derivation of RAP. Alkylation of the hydroxyl (O-alkylation) in either position 28 or 40 was undertaken. Methylation of the C28 hydroxyl led to a compound which still binds well to its immunophilin FKBP12, but exhibits no immunosuppressive activity anymore. Alkylation of the C40 hydroxyl, on the other hand, led to various FKBP12-binding, immunosuppressive derivatives, among which the compound 40-O-(2-hydroxy)ethylrapamycin (RAD) was selected for development. RAD is presently undergoing clinical trials for use in combination with cyclosporine A to prevent acute and chronic rejection after solid organ allotransplantation.
Here we present the 1.8A
X-ray structure of the complex FKBP12/RAD and show a comparison
with the complex FKBP12/RAP. In addition the structural
explanation is shown on why 28-O-methylrapamycin is not
immunosuppressive anymore (and why RAD still is
immunosuppressive), in terms of modelled interactions of the
FKBP12/ligand complexes with the target-protein FRAP (=mTOR).