Methods for selecting functional polypeptides

A method for selecting a functional polypeptide from a repertoire of polypeptides comprising functional and non-functional polypeptides, said functional polypeptides being those which bind to a target ligand at a first binding site and to the same generic ligand at a second binding site, said generic ligand having affinity for a structural feature common to all functional members of the repertoire, said non-functional polypeptides being unable to bind to a target or generic ligand, the method comprising the steps of:

• a) contacting the repertoire with the generic ligand and selecting polypeptides bound thereto, thereby obtaining a first selected pool of polypeptides enriched for said functional polypeptides and comprising a reduced proportion of non-functional polypeptides;
• and
• b) contacting the first selected pool of polypeptides with a target ligand and selecting a population of polypeptides which bind to the target ligand;
• wherein said contacting steps (a) and (b) select polypeptides that bind target ligand at said first binding site and generic ligand at said second binding site.