Conformationally-restricted combinatiorial library composition and method
AssigneePence, Inc.
InventorsMichael E. Houston, Jr., Robert S. Hodges
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Abstract
Combinatorial libraries of different-sequence peptide members is disclosed. The libraries are comprised of stabilized, alpha-helical polypeptides having a similar tertiary structure but different amino acid residues at specific, "variable" positions in the sequence. The polypeptides are stabilized through coiled-coil interactions with other .alpha.-helical polypeptides and/or via intrahelical lactam bridges. Also disclosed are methods for using such libraries to screen for selected macromolecular ligands.
Claims13
A combinatorial library of different-sequence polypeptide members, where each member of the library comprises
- (a) first and second polypeptides bound to one another to form an alpha-helical coiled-coil dimer scaffold characterized by (i) an internal region formed by regularly repeating, invariant, hydrophobic amino acid residues in both polypeptides, (ii) first and second exposed regions formed by regularly repeating amino acid residues in the individual first and second polypeptides, respectively, (iii) a polypeptide length of at least seven residues for each polypeptide, and (iv) a covalent intrachain bond between invariant residues in at least one of the polypeptides, effective to stabilize that polypeptide in its .alpha.-helical conformation, where the scaffold is stabilized by hydrophobic interactions among the subunits in the internal region of the scaffold and the intrachain bond, and
- (b) a unique variation of amino acid residues in the exposed region of at least one of the polypeptides.
Dependencies are inferred from the claim text.