Identification of Novel Immunosuppressant Target(s)

Rapamycin is a promising therapeutic agent because of its potent antiproliferative and immunosuppressive activities. The goal of this project is to identify the cellular target of rapamycin which mediates its antiproliferative/immunosuppressive activity. During Phase I study, we will identify the FKBP-l2 surface residue mutants, i. e., residues involved in protein-protein interaction that confer resistance to rapamycin in yeast, but do not affect drug binding. In Phase II study, we will isolate compensatory mutations in a second protein which restores its interaction with the mutant FKBP-l2/rapamycin complex, i. e., select second site mutations in the target of the FKBP- l2/rapamycin complex. The yeast gene specifying this target will be cloned by complementation of the second site mutations and then used to identify its human counterpart. The outcome of this research addresses one of our major goals: the identification of cellular proteins which are targets for novel therapeutics with antiproliferative-immunosuppressive activity.