Affinity modulation of small-molecule ligands by borrowing endogenous protein surfaces.
A general strategy is described for improving the binding properties of small-molecule ligands to protein targets. A bifunctional molecule is created by chemically linking a ligand of interest to another small molecule that binds tightly to a second protein. When the ligand of interest is presented to the target protein by the second protein, additional protein-protein interactions outside of the ligand-binding sites serve either to increase or decrease the affinity of the binding event. We have applied this approach to an intractable target, the SH2 domain, and demonstrate a 3-fold enhancement over the natural peptide. This approach provides a way to modulate the potency and specificity of biologically active compounds.
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
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Briesewitz
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Ray
T J
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Wandless
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Crabtree
D000595:Amino Acid Sequence; D001665:Binding Sites; D002151:Calorimetry; D003001:Cloning, Molecular; D004926:Escherichia coli; D006801:Humans; D020104:Immunophilins / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D046911:Macromolecular Substances; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013499:Surface Properties; D016559:Tacrolimus / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins
D008024:Ligands; D046911:Macromolecular Substances; D010455:Peptides; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D016559:Tacrolimus