Nucleopeptides with predictable 3D-architectures

Polyamide backbones with nucleo-bases as pendants have gained much attention in view of their potential applications in antisense therapy and immunotherapy. Indeed, such hybrid molecules are insensitive to phosphatase hydrolytic actions, while retaining (or even improving) polynucleotide complexation. By taking advantage of our long-standing experience in the synthesis and 3D-characterization of conformationally constrained alphaamino acids and peptides, particularly those based on C-alpha-tetrasubstituted a-amino acids, we designed and synthesized short, betaturn- or helix-forming alpha-nucleo-peptides. Nucleo-base-containing residues (beta-substituted Ala) were inserted into host, homo-peptide stretches of Aib (alpha-aminoisobutyric acid). The primary structure of the longest peptides were designed in order to allow all nucleo-bases to be aligned on the same face of the helical molecules. These new nucleopeptides are characterized by (1) markedly rigid backbones, (2) helical conformations (usually of the 3–10 type) and (3) high predictability of their 3D-structures. Thus, they might be able to force a complementary polynucleotide chain to adopt unusual conformations Nucleopeptides with a lower percentage of Aib residues were also synthesized. Interestingly, they are able to cross the biological membranes without displaying any significant cytotoxicity. In addition, they exhibit a remarkable resistance to the enzymatic degradation. Therefore, we believe these molecules are promising candidates for the development of new drugs.