HIGH-RESOLUTION SOLUTION STRUCTURE OF 2 MEMBERS OF A CONFORMATIONALLYHOMOGENEOUS COMBINATORIAL PEPTIDE LIBRARY BASED ON THE CLASSICAL ZINC-FINGER MOTIF

We describe the high-resolution structure by NMR of two peptides that belong to a combinatorial library based on the zinc-finger motif. The library represents, to the best of our knowledge, the first example of a conformationally homogeneous peptide library and was obtained by in troducing random residues in five positions of the or-helical portion of a 26-residue 'consensus' peptide (CPI) belonging to the Cys(2)-Hys( 2) zinc-finger family. The result was shown to be a highly hom (Bianch i et al., 1995). The structures of the parent compound (CPI) and of a representative member (CPlm) that was selected by screening the librar y with a monoclonal antibody are compared in detail as an example of t he very high stability of the zinc-finger scaffold upon sequence varia bility. The two peptides exhibit an extremely high degree of structura l similarity. The use of this type of conformationally constrained com binatorial library might represent a step forward in the design of pep tidomimetics, as it considerably accelerates the process of the identi fication of the spatial relationship among the pharmacophoric groups.