MULTIMERIC TETHERED LIGANDS AND THEIR USE IN RECEPTOR-LIGAND INTERACTIONS

摘要

Multimeric tethered ligands are disclosed, comprising a plurality of ligand moieties tethered to a joint moiety, wherein each ligand moiety comprises a ligand for at least one receptor protein having multiple binding sites for the ligand and each ligand moiety is linked by a tether moiety to that joint moiety. Exemplary dimeric tethered ligands are disclosed in which the tether is a simple polymer, polyethylene glycol, which are therefore called "polymer-linked dimers" (PLDs). Exemplary PLDs containing two guanosine 3', 5' cyclic monophosphate (cGMP) moieties are described which are up to 1,000-fold more potent than cGMP in activating cyclic nucleotide-gated (CNG) channels and protein kinases. Each protein responds optimally to a PLD with a different average polymer length, indicating that each has a unique spacing of binding sites. Since optimal ligands are selected empirically, the multivalent tethered ligand strategy allows identification of highly potent and specific agents with no prior structural information about target proteins.