lengths were found for short peptoid sequences as compared to achiral polymers of
similar structure. For longer peptoids, the differences were only minor [68]. More
bulky substituents can help to sterically stabilize such helices, as has been shown by
Blackwell and coworkers [55, 69]. Incorporating the N-1-naphtylethyl side chain,
peptoid helices showed higher K cis/trans values while retaining the overall helix
structure (poly-L-proline type I helix). The authors argued that this would help to
increase the water solubility of such helical peptoids because less helix-inducing
monomers are necessary. However, it may be argued that the 1-naphtylethyl
residues imposed a much more pronounced hydrophobic character as compared
to the 1-phenylethyl residues. As has been discussed before, N-aryl substituents
stabilize the trans-conformation in peptoids. Regarding the helix, this translates
into poly-L-proline type II helices, as predicted and confirmed by Kirshenbaum and
coworkers [56].
Several approaches have been reported for chemical modification of peptoid
helices [70–72]. Functionalized helices are interesting for fostering formation of
higher-order structures or modifying the solubility. The chemical modification can
also be used conveniently to stabilize peptoid helices. For example, Wennemers
and colleagues studied helices of 4-azidoproline (Azp) [73]. Although (4R)Azp
stabilized the poly-L-proline type I helix, its enantiomer (4S)Azp destabilized
it. Modification of the peptoid was conveniently achieved by click chemistry.
Kirshenbaum et al. introduced mutually reactive groups (alkyne and azide) at i
and i+3 positions of helicogenic peptoid sequences. By coupling i and i+3 moieties
together, very short peptoids were stabilized towards helical structures. Using this
approach, the authors claim to be able to reduce the amount of helicogenic building
blocks. However, this advantage is partly negated by the need to incorporate at least
two residues to stabilize the helix [70].
Zuckermann et al. described a different approach and introduced 1-phenylethyl
peptoid side chains with functional groups in the para-position of the phenyl ring
(Fig. 7). Thus, the functionalities are present at the outer perimeter of the peptoid
helices. As such, it allows mimicking of the interaction between α-helices in coiled
coils and helix bundles in proteins [74–76].
Bra ¨se, Muhle-Goll and coworkers reported on functional peptoid helices [77]. In
order to create cell-penetrating peptoids, butylamine residues were incorporated
into peptoids. NMR spectroscopy and molecular modeling revealed an extended
pseudo-helical structure with predominant cis-conformation in the backbone. The
electrostatic repulsion between the side chains leads to maximization of the spacing
of the ammonium residues and thus dominates the conformation of the peptoid.
With a pitch of 7.7 A ˚ , the charge distribution is somewhat less dense compared to
α–helical peptides. Nevertheless, the peptoids were effective transporters, similar to
other cell-penetrating peptides.
Kang et al. used a peptoid helix to position porphyrins in different relative
orientations. It was found that whether the porphyrins were positioned cofacial,
slipped-cofacial, or unstructured had profound effects on the degree of
J-aggregation, the resulting color, and excitonic coupling [78]. The authors suggest
Peptoids for Biomimetic Hierarchical Structures
399
similar structure. For longer peptoids, the differences were only minor [68]. More
bulky substituents can help to sterically stabilize such helices, as has been shown by
Blackwell and coworkers [55, 69]. Incorporating the N-1-naphtylethyl side chain,
peptoid helices showed higher K cis/trans values while retaining the overall helix
structure (poly-L-proline type I helix). The authors argued that this would help to
increase the water solubility of such helical peptoids because less helix-inducing
monomers are necessary. However, it may be argued that the 1-naphtylethyl
residues imposed a much more pronounced hydrophobic character as compared
to the 1-phenylethyl residues. As has been discussed before, N-aryl substituents
stabilize the trans-conformation in peptoids. Regarding the helix, this translates
into poly-L-proline type II helices, as predicted and confirmed by Kirshenbaum and
coworkers [56].
Several approaches have been reported for chemical modification of peptoid
helices [70–72]. Functionalized helices are interesting for fostering formation of
higher-order structures or modifying the solubility. The chemical modification can
also be used conveniently to stabilize peptoid helices. For example, Wennemers
and colleagues studied helices of 4-azidoproline (Azp) [73]. Although (4R)Azp
stabilized the poly-L-proline type I helix, its enantiomer (4S)Azp destabilized
it. Modification of the peptoid was conveniently achieved by click chemistry.
Kirshenbaum et al. introduced mutually reactive groups (alkyne and azide) at i
and i+3 positions of helicogenic peptoid sequences. By coupling i and i+3 moieties
together, very short peptoids were stabilized towards helical structures. Using this
approach, the authors claim to be able to reduce the amount of helicogenic building
blocks. However, this advantage is partly negated by the need to incorporate at least
two residues to stabilize the helix [70].
Zuckermann et al. described a different approach and introduced 1-phenylethyl
peptoid side chains with functional groups in the para-position of the phenyl ring
(Fig. 7). Thus, the functionalities are present at the outer perimeter of the peptoid
helices. As such, it allows mimicking of the interaction between α-helices in coiled
coils and helix bundles in proteins [74–76].
Bra ¨se, Muhle-Goll and coworkers reported on functional peptoid helices [77]. In
order to create cell-penetrating peptoids, butylamine residues were incorporated
into peptoids. NMR spectroscopy and molecular modeling revealed an extended
pseudo-helical structure with predominant cis-conformation in the backbone. The
electrostatic repulsion between the side chains leads to maximization of the spacing
of the ammonium residues and thus dominates the conformation of the peptoid.
With a pitch of 7.7 A ˚ , the charge distribution is somewhat less dense compared to
α–helical peptides. Nevertheless, the peptoids were effective transporters, similar to
other cell-penetrating peptides.
Kang et al. used a peptoid helix to position porphyrins in different relative
orientations. It was found that whether the porphyrins were positioned cofacial,
slipped-cofacial, or unstructured had profound effects on the degree of
J-aggregation, the resulting color, and excitonic coupling [78]. The authors suggest
Peptoids for Biomimetic Hierarchical Structures
399