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. In the subject methods, 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 that exhibits at least one of improved affinity, specificity or selectivity as compared to the corresponding free drug. The subject methods and compositions find use in a variety of therapeutic applications.

Administering bifunctional molecules containing a drug moiety and presenter protein ligand for therapy

Factor Va increases the affinity of factor Xa for prothrombin: a binding study using a novel photoactivable thiol-specific fluorescent probe.

Bifunctional molecules and methods for their use are provided The subject bifunctional molecules are conjugates of a drug moiety and a pharmacokinetic modulating moiety, where these two moieties are optionally joined by a linking group The bifunctional molecules are further characterized in that they exhibit at least one modulated pharmacokinetic property upon administration to a host as compared to a free drug control The subject bifunctional molecules find use in a variety of therapeutic applications

Modulating a pharmacokinetic property of a drug by administering a bifunctional molecule containing the drug

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.

Synthetic bifunctional molecules containing a drug moiety and presenter protein ligand

Bifunctional inhibitor molecules and methods for their use in the inhibition of protein-protein interactions are provided. The subject bifunctional inhibitor molecules are conjugates of a target protein ligand and a blocking protein ligand, where these two moieties are optionally joined by a linking group. In the subject methods, an effective amount of the bifunctional inhibitor molecule is administered to a host in which the inhibition of a protein-protein interaction is desired. The bifunctional inhibitor molecule simultaneously binds to its corresponding target and blocking proteins to produce a tripartite complex that inhibits the target protein-protein interaction. The subject methods and compositions find use in a variety of applications, including therapeutic applications.

Bifunctional molecules and their use in the disruption of protein-protein interactions

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2887%2980965-1

A new carbene based heterobifunctional reagent Photochemical crosslinking of aldolase

Synthesis of a radioactive photoactivable heterobifunctional reagent, N- oxysuccinimide ester of 2-( 14 C)glycyl carboxy-9-diazofluorene is described. This reagent on photolysis gives rise to a reactive carbene which rapidly inserts into solvents like methanol. The probe can be easily linked to aldolase which on photolysis gives rise to aldolase dimer, trimer and tetramer depending on the density of linked probe. This probe has also been linked to concanavalin A. The radioactive concanavalin A so obtained was incubated with erythrocyte ghosts and photolysed. The membrane protein analysis by gel electrophoresis indicated that concanavalin A has been covalently crosslinked to band 3.

/pdf/a-new-radioactive-diazofluorene-based-heterobifunctional-40v5otw6uq.pdf

H. F. Batliwala

Papers

A new carbene based heterobifunctional reagent Photochemical crosslinking of aldolase

A new radioactive diazofluorene based heterobifunctional reagent