| abstract |
Bifunctional molecules and methods for their use in the production of binary complexes in a host are provided. The bifunctional molecule is a conjugate of a drug moiety and a presenter protein ligand. The molecular weight of the bifunctional molecule is preferably less than about 5000 daltons, and the drug moiety may have a molecular weight of from about 50 to 2000 daltons. The drug moiety and presenter protein ligand may be covalently linked directly or through a linking group. The drug moiety binds to a drug target such as a protein and the presenter protein ligand binds to a presenter protein that is not the drug target such as extracellular or intracellular protein. Presenter proteins include peptidyl prolyl isomerase (FKBP), Heat Shock Protein 90 (Hsp90), steroid hormone receptors, cytoskeletal proteins, albumin and vitamin receptors. When the presenter protein is FKBP, ligands include FK506, rapamycin and cyclosporin A which may have an introduced functional group such as hydroxyl, amino, carboxyl, aldehyde, carbonate, carbamate, azide, thiol or ester for attaching the drug moiety. In the methods of use, an effective amount of the bifunctional molecule is administered to the host. The bifunctional molecule binds to the presenter protein to produce a binary complex such that the drug exhibits at least one of improved affinity, specificity or selectivity as compared to the corresponding free drug. The methods and bifunctional molecules find use in a variety of therapeutic applications. |