Functionalized Bis-Peptides

About

Technology: The present invention relates to bis-peptides containing functional groups and also to methods for the acylation of hindered amines.   Background: The need for new chemical agents that can modulate protein function in vivo provides a fundamental challenge for chemists. Molecules that are intermediate in size between small molecule drugs (<600 Daltons) and protein therapeutics could provide new chemical entities capable of binding to the large, flat protein surfaces required to modulate a protein function. Bis-peptides potentially could meet this need, but synthetic methods for preparing such compounds have not been fully developed, particularly with respect to bis-peptides that contain one or more functional groups that project in defined three dimensional constellations. This invention provides a route to such compounds.   Technology:  We have now discovered a synthetic methodology for the assembly of bis-peptides that makes possible for the first time the controlled placement of functional groups of different types along the length of a bis-peptide molecule. These functional groups can be pendant to the bis-peptide chain, which can be dimeric, oligomeric or polymeric in character. Pre-organized, functionalized bis-peptides can be designed using relatively simple molecular modeling which have three-dimensional structures that are immune to denaturation, thus potentially providing significant advantages over proteins, DNA, RNA and unnatural foldamers. The control of functional group presentation can be determined by the structure of the bis-amino acids used to prepare the bis-peptides. The three-dimensional structure of the bis-peptide backbone and thus the relative orientation of the side-chains (the functional groups) can be varied as desired by controlling the stereochemistry and the sequence of the monomers utilized in constructing the bis-peptide. The constellations of functional groups in the bis-peptide can mimic active sites of proteins and protein binding surfaces. The bis-peptides of the present invention are highly preorganized macromolecules (e.g., having molecular weights of 600 to 2000 Daltons), which can be designed to recapitulate the presentation of the relevant side chains of one partner of a protein-protein interaction, bind the other partner and mediate a biological response.