Design of Peptidic Foldamer Helices: A Stereochemical Patterning Approach

Abstract

Assembly language: The programmed sequences of stereochemical building blocks lead to novel biomimetic helices. The rational design approach offers new possibilities for creating periodic secondary structures.

Foldameric β‐H18/20P Mixed Helix Stabilized by Head‐to‐Tail Contacts: A Way to Higher‐Order Structures

“…For stereochemical reasons, inversion of the backbone configurations of the sequence results in the mirror image (2), which should form an M-type helix (left-handed). According to the stereochemical patterning approach introduced earlier, [30,31] this operation is equivalent to shifting of the backbone configuration pattern with a monomer unit. Our starting hypothesis was that manipulation of either the C or N terminus would result in a deterministic transfer of chiral information along the chain by changing the helix sense, but that the H10/12 helical structure would be retained.…”

“…Peptidic foldamers have the ability to form helices with relatively large diameters, [30,31] which, in theory, can participate in stable axial (e.g., head-to-tail) interactions through backbone hydrogen bonds and side-chain interactions. This phenomenon can be observed in gramicidin A, for example, in which axial self-recognition takes place in the membrane environment.…”

Investigation of protein–ligand interactions of targets with solvent exposed binding sites

“…H14 or H10/12. The secondary structure and self-assembly of peptidic foldamers can be controlled via the β-amino acid sequence and backbone stereochemistry, 150 and also tuned via the side-chain chemistry. 151 Moreover, their resistance to enzymatic degradation has been demonstrated, [152][153][154] which is a very important feature for a drug scaffold.…”

“…The conformational sampling was carried out by using the hybrid Monte Carlo (MC)-Molecular Dynamics (MD) simulation as described in ref. [150].…”

“…Our goal was to target Aβ1-42 oligomers with foldamers, which, thanks to their diversity, 189 tunable secondary structure and resistance to enzymatic degradation, [152][153][154] have emerged as a novel class of drug scaffolds. With appropriate backbone stereochemistry 150 and by incorporating 2-3 hydrophilic amino acids into the sequence, short water-stable peptidic foldamers can be constructed, which can direct 3-4 side-chains towards a flat protein surface. In general, they can exhibit only weak (K d >10 µM) binding, which can be detected by NMR methods.…”