Selective disruption of interactions between helical domains emerged as attractive target for drug discovery.[1] However, protease susceptibility of natural peptides limits their clinical use as drugs. The design of foldamers strives to solve this problem of proteolytic degradation. Foldamers that are composed of β- and γ-amino acids mimic the self-assembly of native peptides.[2] Moreover, β/γ-peptides display similar H-bonding patterns to all-α-peptides. They present functional groups in a predictable manner[3] and the incorporation of β- and γ-amino acids leads to increased stability towards proteolytic degradation.[4]
In previous work, we investigated the interactions between an α/β/γ-chimera and all-α-peptides within the quaternary structure of a tetrameric coiled-coil motif.[1,5] In the course of this research, we presented a Cys/Phe-motif that selectively binds to the β/γ-module and exhibits comparable stability to their parental systems. MD simulations revealed the formation of an interstrand H-bond between the thiol-residue of Cys and the unbound backbone carbonyl of the β/γ-pentad sequence.[5] Our latest research focusses on structural studies such as crystallization strategies and NMR to examine the stabilizing effect of the interstrand H-bond of the heteroassembly. Furthermore, modular substitution of α-helical segments of the tetrameric coiled coil-system by β/γ-modules is performed and the obtained structural properties are investigated.