De Novo Design of Proteins - Peptide and Protein Design for Biopharmaceutical Applications - page 232

6.5 FOLDAMERS

Foldamers are non-natural oligomers that adopt a secondary structure by
stabilization through noncovalent bonds (Figure 6.9). These artificial
molecules are designed to mimic proteins and other biopolymers by
folding into well-defined conformations, including helices and b-sheets
(for a review, see [147]). Probably the most prominent members of
biomimetic foldamer oligomers are the b-peptides, which are assembled
from homologated amino acids, i.e. a CH 2 is inserted between carbonyl
and amino moieties. Other building blocks include cyclic structures, for
example cyclopentanes. Foldamers that mimic proteins can be considered
peptidomimetics. For an overview of peptidomimetics and other aspects
of foldamers, see Chapter 3 by Maes and Tourw ´.

3 2 1

R O

β

H

α

β 3 -peptide

Figure 6.9 Example of a foldamer unit

Foldamers are peptidomimetics and so far primarily short sequences
have been assembled, thus foldamers will only be mentioned briefly here
(for a review, see [148]). However, a few applications to the construction
of protein mimics have been reported. Foldamers of b 3 -amino acids have
their side chain on C3 relative to the carbonyl, while b 2 -amino acids have
it at C2. As for peptides assembled from a-amino acids, the amide bonds
are rigid. Foldamers assembled from b-amino acids can be stabilized by
hydrogen bonds, forming either a 14-member ring between the NH at
residue i and the carbonyl at i þ 2, which forms a 14-helix that can be
either left- or right-handed [149]. b 3 -amino acids derived from proteino-
genic L -amino acids have a high propensity to form left-handed 14-helices
[150]. The 14-helix has approximately three residues per turn, i.e. a
three-residue repeat, giving an approximately triangle-like helical wheel
presentation. In a b-peptide 14-helix, the C3 atoms of residues i and i þ 3
are close (4.8 ˚ compared to 6.3 ˚ in an a-helix) and side chains projecting
from these positions are nearly parallel to one another [151]. Also, the