Access to poly-beta-peptides with functionalized side chains and end groups via controlled ring-opening...

Poly-beta-peptides are attractive for biomedical applications because the backbone is similar enough to that of proteins for biocompatibility, but the backbone is sufficiently unnatural that these polymers evade proteolytic degradation. Prior investigations of poly-beta-peptides have been hindered by two principal limitations: (1) most known examples are insoluble, and (2) the range of accessible side chain functionality has been quite limited (mostly simple hydrocarbon units). The present study describes innovations in poly-beta-peptide synthesis that enable the preparation of diversely functionalized examples and provide the basis for broad exploration of the properties and applications of these nylon-3 materials. We describe several beta-lactams with a protected amino group in their side chain that readily undergo ring-opening polymerization (ROP). These monomers are available in large quantities via N-chlorosulfonylisocyanate (CSI) cycloaddition reactions with functionalized alkenes; previously CSI reactions have been limited to alkenes with hydrocarbon substituents. Postpolymerization deprotection of the amino groups leads to water-soluble poly-beta-peptides. In addition, we introduce a simple co-initiation strategy that allows placement of a wide variety of functional groups at the N-termini of poly-beta-peptide chains. ROP involving the new beta-lactams and co-initiation strategy exhibits characteristics of a controlled polymerization and enables the preparation of amphiphilic block copolymers. We have recently shown that cationic copoly-beta-peptides made available by these innovations mimic the selective antibacterial activity of host-defense peptides; the results described here provide the foundation for further exploration of this valuable activity and for the pursuit of other biological applications such as DNA/siRNA delivery and tissue engineering.