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Peptoid architectures: elaboration, actuation, and application
Barney Yoo and Kent Kirshenbaum
Peptoids are peptidomimetic oligomers composed of
N-substituted glycine units. Their convenient synthesis enables
strict control over the sequence of highly diverse monomers
and is capable of generating extensive compound libraries.
Recent studies are beginning to explore the relationship
between peptoid sequence, structure and function. We
describe new approaches to direct the conformation of the
peptoid backbone, leading to secondary structures such as
helices, loops, and turns. These advances are enabling the
discovery of bioactive peptoids and will establish modules for
the design and assembly of protein mimetics.
Address
Department of Chemistry, New York University, 100 Washington Square
E., Room 1001, New York, NY 10003, United States
Corresponding author: Kirshenbaum, Kent (kent@nyu.edu)
Current Opinion in Chemical Biology 2008, 12:714–721
This review comes from a themed issue on
Model Systems
Edited by Helma Wennemers and Ronald T. Raines
Available online 9th September 2008
1367-5931/$ – see front matter
# 2008 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.cbpa.2008.08.015
Introduction
A strong foundation has been established for constructing
synthetic oligomers that exhibit conformational ordering.
These compounds, dubbed foldamers, hold substantial
promise for applications in biomedicine and materials
science [1]. The oriented display of oligomer sidechains
bearing specified chemical functionalities enables their
use for molecular recognition applications [2]. Various
foldamers have been described as effective protein bind-
ing agents, potentially emulating antibodies [3]. Folda-
mer compounds may soon prove capable of carrying out
many additional functions typically exhibited by proteins,
including biologically relevant catalysis and transport.
Recent efforts to develop increasingly sophisticated fol-
damer architectures are demonstrated by a profusion of
relevant advances. These studies are expanding the capa-
bilities of molecular design and may also provide insights
regarding general principles of macromolecular self-
assembly and biopolymer function [4].
Foldamer design criteria that will prove particularly valu-
able for Chemical Biology applications include
Current Opinion in Chemical Biology 2008, 12:714–721
 efficient synthesis of specified heterooligomer
sequences of substantial chain length, preferably on
solid phase
 access to chemically diverse monomer sidechains
 conformational stability and conformational diversity
 predictable sequence–structure–function relationships
 water-solubility and biocompatibility
 favorable pharmacological characteristics, including
resistance to degradation in vivo and cell membrane
permeability
 potential for biomolecular recognition
This review provides a synopsis of recent advances for a
particular family of peptidomimetic foldamers. Peptoids,
oligomers of N-substituted glycine, are an instructive
example of foldamer compounds as they embody many of
the attributes listed above [5]. A notable exception is that
sequence–structure–function relationships for peptoids
remain somewhat opaque and largely unexplored. Given
that these relationships also remain a lasting and
formidable challenge in the area of de novo protein
design, the shortcomings for peptoids are not overly
vexing. Indeed, advances in peptoid design are accumu-
lating rapidly, as detailed herein.
Peptoid forms
Primary sequence
The study of peptoid oligomers has been propelled by a
remarkably efficient ‘submonomer’ protocol for their
synthesis. Each monomer unit can be added on solid
phase through sequential steps of bromoacetylation fol-
lowed by nucleophilic addition of a primary amine. Iter-
ation of these high-yielding reactions can be automated,
allowing the sequence-specific assembly of the polya-
mide products up to 48 residues in length. Chemical
diversity of the sidechains is readily obtained by variation
of the amine synthons. As distinct from peptide synthesis,
there is no general requirement for protecting groups.
In addition to the intrinsic chemical diversity obtained
through oligomer synthesis, strategies have also been
established for post-oligomerization chemical modifi-
cation of suitably reactive peptoids. Sidechain function-
alities including thiol, aldehyde, and hydrazide groups
were installed by straightforward extension of the sub-
monomer protocols and used as sites for chemoselective
conjugation reactions [6]. Additionally, bioorthogonal
chemical modification of peptoid azidoalkyl or propargyl
sidechains can also be implemented by means of Cu-
catalyzed azide/alkyne [3 + 2] cycloaddition reactions
[7,8]. This ‘click chemistry’ approach has enabled the
site-specific multivalent presentation of interesting
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groups such as nucleobases, steroids, and metallocenes
[7,9,10].
Long-term goals in the design of peptoid architectures
will include mimics of complex protein folds. As is the
case for the total chemical synthesis of proteins, such
constructions will necessitate segment condensation
strategies. The aforementioned chemoselective conju-
gation reactions have proven effective for performing
peptoid ligations. These studies have afforded peptoids
joined through hydrazone, oxime, disulfide [11], and
triazole [7] linkages. Peptoid segments have been joined
through native amide backbone linkages created via
protease-catalyzed ligation reactions between peptoid
C-terminal thioesters and N-terminal amine groups
[12]. These reactions were adapted to concatenate short
peptoid oligomers into polydisperse macromolecular pro-
ducts with molecular weights up to 20 kDa [12].
Secondary structures
Peptoids were initially evaluated by Zuckermann and
colleagues in the early 1990s in small-molecule combi-
natorial libraries as part of drug discovery efforts. It was
anticipated that peptoid oligomers might be confor-
mationally labile owing to the flexibility of the backbone
methylene groups and the inability to establish hydrogen
bond interactions that could define repeating secondary
structures. Nevertheless, experimental and compu-
tational efforts soon established peptoids as an early
example of foldamer compounds. These studies revealed
that peptoids could form helical secondary structures in
which the presence of bulky chiral sidechains, such as in
N-(1-phenylethyl)glycine monomers, exert a local steric
influence restricting the accessible backbone dihedral
angles [13]. Solution NMR [14] and X-ray crystallography
[15] established that the peptoid helix features repeating
cis-amide bonds and a helical pitch of about three residues
per turn, thus resembling a polyproline type I helix.
Peptoid sequences as short as pentamers can exhibit this
secondary structure (Figure 1a).
Although appreciable steric bulk of the tertiary amide N-
alkyl substituents can favor cis amide bonds, this ener-
getic preference is modest, resulting in substantial cis/
trans amide bond isomerization and conformational
heterogeneity. The kinetics of these rearrangements
have been carefully evaluated by NMR studies of short
peptoid dimers and trimers, revealing that the transitions
are slow on the NMR time scale, which complicates
NMR analysis of larger peptoid oligomers [16]. The
Blackwell group has explored interactions between the
peptoid backbone amides and various aromatic side-
chains, finding evidence for n ! p* effects that can be
modulated to alter the ratio of cis/trans amide bond
conformers [17]. It is not yet evident if the observed
energy differences between cis and trans amide
bonds (generally up to 1.4 kcal/mol) will be sufficient
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Peptoid architectures Yoo and Kirshenbaum 715
to establish conformational homogeneity in larger oligo-
mers. Experiments to address this issue are ongoing in
the Blackwell group.
Local steric and stereoelectronic influences may prove
inadequate to define more complex peptoid architectures.
Long-range interactions, such as hydrogen bond net-
works, electrostatic and hydrophobic interactions have
been effective in constraining diverse foldamer structures
[1], and may also play a role in defining peptoid con-
formation. The Barron group, upon conducting a survey
of helical N-(R)-(1-phenylethyl)glycine homooligomers
of varying chain lengths, discovered anomalous circular
dichroism (CD) spectra for the peptoid 9 mer in aceto-
nitrile, suggestive of a novel secondary structure type
[18]. Further scrutiny by solution NMR studies revealed a
‘threaded loop’ arrangement in which the N-termini and
C-termini were held in proximity through the influence of
hydrogen bond interactions [19] (Figure 1b). Solvopho-
bic effects were also operative, leading to sequestration of
polar amide groups within the interior of the loop. In an
elegant demonstration that subtle sequence variations
can influence long-range structural interactions, the
Blackwell group has substituted N-(1-pentafluoropheny-
lethyl)glycine residues into the 9 mer, showing position-
sensitive changes in secondary structure that were attrib-
uted to alterations in the strength of neighboring hydro-
gen bonds [20].
Long-range interactions can also be enforced through the
introduction of covalent constraints. Macrocyclization is
proving to be a highly effective strategy for defining
peptoid conformations. Initial efforts involved the tether-
ing of azide and alkyne groups through ‘click chemistry’
reactions [21]. A series of such sidechain to sidechain
linkages were installed at varying distances within the
context of helical peptoid octamers. CD and NMR evi-
dence indicated enhanced conformational ordering when
the macrocyclic constraint was installed at sequence
positions matching one turn of the helix (i, i + 3).
The formation of head-to-tail peptoid macrocycles has
also been demonstrated [22]. Covalent constraints were
generated between the N-terminal amino group and C-
terminal carboxylic acid through standard amide bond
formation. These reactions were conducted on diverse
peptoid sequences from pentamers to 20 mer and pro-
ceeded with remarkable alacrity, affording high yields of
the corresponding macrocycles (15–60 atoms) within
5 min at room temperature. X-ray crystal structures were
obtained of a cyclic hexamer and octamer. The peptoid
backbones formed planar hairpin structures in which the
turn units provided good structural matches to the type I
and type III beta turns of proteins (Figure 1c). The
backbones exhibited a combination of cis and trans amide
bonds, which were notable for their significant deviations
from planarity.
Current Opinion in Chemical Biology 2008, 12:714–721
716 Model Systems

Figure 1

High resolution studies of peptoid oligomer secondary structures. (a) The peptoid N-(R)-(1-cyclohexylethyl)glycine pentamer forms a helix with
repeating cis amide bonds, resembling a polyproline type I peptide secondary structure [15]. (b) The peptoid N-(S)-(1-phenylethyl)glycine 9 mer forms
a ‘threaded loop’ in acetonitrile. Hydrogen bonds (in green) and solvophobic interactions direct the formation of the compact structure [19]. (c) The
peptoid cyclo[N-(benzyl)glycine-N-(methoxyethyl)glycine]3 hexamer macrocycle forms a planar hairpin including both cis and trans amide bonds. The
turn units are homologous to the type I and type III beta turns in proteins [22].

Cyclic peptoid pentamers can also be constructed using a
series of Ugi 4-component and 3-component reactions to
first assemble the linear oligomer and then establish the
macrocycle [23]. The influence of macrocyclization to
define conformation has recently been demonstrated in
beta-peptoids (N-substituted beta-alanine oligomers). A
crystal structure has been obtained of the head-to-tail
tetramer (16 atom) macrocycle [8], revealing that the
covalent constraint enforces an ordered conformation of
repeating cis amide bonds in what might otherwise be
expected to be a highly flexible oligomer system [24].
Similarly, turn elements were designed in hybrid oligo-
mers incorporating peptoid sequences and their confor-
mations studied by NMR and CD [25,26].
Beyond secondary structures
Research directed by Zuckermann and Dill has pursued
the self-assembly of peptoid secondary structure
elements into more complex folds. Preliminary efforts
have demonstrated that individual amphiphilic peptoid
helices can associate, presumably in bundles, to form a
hydrophobic core [27]. Similar helices were subsequently
ligated to form disrecte multihelical assemblies [11],
which have recently been equipped with multiple thiol

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Figure 2
Assemblies of peptoid secondary structures. (a) A helix–loop–helix
peptoid mimic of a metalloprotein. Thiol and imidazole sidechain groups
are displayed on the helix to create an organized coordination
environment for zinc. Metal binding induces a compact assembly of the
helices [28]. (b) ‘Nanotube’ structures in the crystal lattice of a
macrocyclic peptoid octamer are formed upon stacking of the peptoid
backbone without the influence of hydrogen bonds [22].
and imidazole sidechains to organize sites for zinc coordi-
nation [28] (Figure 2a). These peptoid macromolecules
may begin to mimic some of the features of metallopro-
teins and suggest a path toward catalytically active pep-
toids. In a similar pursuit, multidentate metal ligands
such as hydroxyquinoline groups have also been installed
as peptoid sidechains [29].
X-ray crystallography reveals that peptoid macrocycles
exhibit highly regular stacking of the planar backbones in
the solid state [22] (Figure 2b). It is notable that the
peptoids assemble in this manner despite the absence of
any hydrogen bonds that would direct the backbones to
form such tube-like arrays.
Peptoid dynamics
Extensive efforts have focused on identifying foldamer
sequences with well-defined or even rigid conformations.
For example, ESR studies confirm that the inclusion of
bulky chiral sidechains can mitigate peptoid dynamics, as
revealed in the distance distribution profiles of peptoid
helices bearing nitroxide spin probes [30]. However,
biopolymers often undergo structural rearrangements in
response to ligand binding or variations in their environ-
ment. The compact helical assemblies studied by Lee
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Peptoid architectures Yoo and Kirshenbaum 717
et al. undergo cooperative transitions to less compact
forms in response to changes in solvent polarity, evoking
similarities to protein denaturation events [11]. Similarly,
the threaded loop peptoid 9 mer becomes more poorly
ordered upon addition of hydrogen bonding solvents
[19]. Such results suggest that peptoids can be designed
to respond to environmental stimuli. Shin has utilized
protected alpha amino acids as submonomer reagents to
synthesize peptoids bearing bulky chiral sidechains that
include carboxylic acid groups [31]. These oligomers
display intense circular dichroism signals in an acidic
pH regime but undergo dramatic rearrangements at neu-
tral pH.
Peptoids bearing photoresponsive azobenzene sidechains
have been studied [32]. As anticipated, these compounds
undergo rapid isomerization of sidechain conformation
upon photo-irradiation. It is somewhat disappointing,
however, that the structural change of the azobenzene
sidechain does not appear to be communicated to per-
turbations in the backbone, as evaluated by CD. It may be
relevant that the azobenzene groups are present as N-aryl
glycine monomer units (in contrast to the N-alkyl glycines
previously studied). The distinct structural features
associated with N-aryl glycine units are under investi-
gation.
Peptoid functions
There are many promising avenues for peptoids as tools
in Chemical Biology (Figure 3). Some of these opportu-
nities exist currently through the ability to synthesize and
assay diverse peptoid primary sequences, whereas other
applications may depend on continuing development of
peptoid secondary and tertiary structures.
For xenobiotic agents to fully engage cellular targets, they
must be capable of penetrating the cell membrane. Pep-
toids are well suited in this regard, as they have good cell
permeability characteristics in comparison with peptides.
This feature may be due to the diminished energetic
penalty for desolvating tertiary amides [33,34]. It is there-
fore not surprising that peptoids have been evaluated as
intracellular transporters for drugs and nucleic acids
[35,36,37]. Notable advances include the development
of cationic peptoids conjugated to phospholipid head-
groups. These ‘lipitoids’ have been shown to be effective
transfection agents for short interfering RNA oligonucleo-
tides, permitting specific gene silencing [38]. Membrane
permeability has similarly facilitated the design of pep-
toid-based transcription factor mimics, allowing for upre-
gulation of targeted genes [39].
Since the introduction of peptoid combinatorial libraries,
there have been many independent discoveries of oligo-
mers that bind specific biomolecular targets, particularly
protein receptors [5]. A current focus in molecular
pharmacology is the identification of peptoids or other
Current Opinion in Chemical Biology 2008, 12:714–721
718 Model Systems

Figure 3

Bioactive peptoid sequences. (Blue) A peptoid antagonist of the vascular endothelial growth factor receptor 2—a target for cancer therapeutics [3].
(Green) A ligand of the protooncogene Crk identified from a 100 million member synthetic peptoid library [45]. (Violet) A helical amphiphilic mimic of
the bioactive peptide magainin—a potential antimicrobial agent [46]. (Black) A lipitoid—a cationic peptoid conjugated to a phospholipid head group.
Lipitoids are effective transfection reagents for short interfering RNA oligonucleotides—a potential agent for gene silencing protocols [38].

foldamers that can antagonize protein–protein inter-
actions [40,41]. Appella and colleagues have developed
peptoids that mimic an alpha-helical sequence present at
a protein–protein interface to antagonize the interaction
between hDM2 and p53, an important target for cancer
therapeutics [42].
Peptoids have proven valuable in the search for protein
recognition agents, as their synthesis is amenable to
generating extensive compound libraries. In practice,
the challenging aspect of these studies may be the design
of effective screening protocols to fully exploit peptoid
chemical diversity. The Kodadek group has recently
developed highly efficient on-bead assays to discover
promising peptoid oligomers that inhibit proteosome
activity [43]. They have also identified peptoids that
act as antagonists of the VEGF Receptor 2 [3,44], using
an elegant cell-based screening approach in which two
cell types were labeled with differently colored quantum
dots.
The Harbury group has innovated techniques for the
synthesis of large libraries of peptoid oligomers indivi-
dually associated with specific DNA sequences, enabling
amplification of compound hits. The completely abiotic
approach is analogous to peptide phage display tech-
niques [45]. A compelling proof of principle was the
discovery of six novel ligands of the N-terminal SH3
domain of the protein Crk that were amplified and
identified from a library of 108 peptoid compounds.
Apart from the broad screening of peptoid sequences,
other biomedical applications of peptoids may rely
explicitly on compounds with well-organized secondary

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structure. For example, the Barron group has pursued a
structure-based approach toward peptoid mimics of
bioactive alpha-helical peptides. One area of success
has been the discovery of amphiphilic helical peptoids
that mimic the natural antimicrobial peptide magainin.
Peptoid sequences were found to inhibit a range of
Gram-negative and Gram-positive bacteria and are
currently being studied in vivo [46]. Other helical
peptoid sequences are being evaluated as mimics of
lung surfactant peptides [47]. Both of these discoveries
potentially address important clinical applications.
Cyclic peptide/peptoid hybrids, or ‘peptomers’, have
been designed as modulators of bacterial quorum
sensing, in which the presence of the macrocyclic
conformational constraint may be important in their
function [48].
There are some caveats regarding peptoids as mimics of
bioactive peptides. The simple shifting of sidechain
types from peptide sequences to the corresponding
peptoid N-substituent positions may not be a generally
effective strategy that maintains native binding inter-
actions. In addition, counterintuitive results may arise
in which enhancing the designed peptoid secondary
structure content does not necessarily yield improved
activities [42,46]. Finally, peptidomimetic com-
pounds identified in screening efforts do not always
bind to previously anticipated sites on their protein
targets [44].
Peptoid prospects
Rational design of increasingly complex peptoid archi-
tectures is predicated on developing an improved un-
derstanding of the accessible permutations of peptoid
conformations. This knowledge is still rudimentary. For-
tunately, the set of high-resolution peptoid oligomer
structures is (finally!) beginning to grow. The prospects
are certainly encouraging, as peptoid structures progress
beyond simple helices to also include various turns and
loops [19,22,26]. It is now possible to contemplate
integrating these secondary structural elements into more
elaborate folds, such as helical bundles [11,28].
In addition to peptoids as protein ligands, new appli-
cations are arising, such as developing peptoids as bio-
compatible materials. For example, peptoids may be used
to create films or surface coatings [49,50,51]. Peptoids
may also prove valuable as scaffolds for precise multi-
valent displays [7,8,9].
It will be important to improve the ability to constrain and
predict peptoid conformation. This will include discover-
ing how different sequences can be used to control
interactions such as stereoelectronic effects and sidechain
to main chain hydrogen bonding [17,31]. The influence
of new monomer types, such as N-aryl glycines and
extended peptoids, are also under investigation [32,52].
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Peptoid architectures Yoo and Kirshenbaum 719
Computational methods are likely to play an increasingly
important role in predicting peptoid conformation. It is
notable that the observed phi and psi backbone dihedral
angles for different peptoid structures are remarkably
similar. Instead, control over the variable amide bond
conformers may be crucial, particularly as this omega
dihedral angle can exhibit unusual non-planar geometries
[22]. A thorough computational energy analysis of back-
bone dihedral angles and sidechain rotamer libraries may
yield improved tools for peptoid design.
Having established a sturdy foundation, it now appears
that constructions of peptoid architectures, along with
other foldamer systems, are in rapid ascent.
Acknowledgements
This work was supported by an award from the NSF (CAREER #0645361).
KK thanks Irwin ‘Tack’ Kuntz, Ken Dill, and Ronald Zuckermann for
mentorship in molecular design and the synthesis of biomimetic polymers.
Figure 2A kindly provided by R. Zuckermann. KK acknowledges the
students working both in his lab and elsewhere for deftly translating peptoid
blueprints into fully realized constructions.
References and recommended reading
Paper of particular interest, published within the period of review, have
been highlighted as:
 of special interest
 of outstanding interest
1. Huc I, Hecht S (Eds): Foldamers: Structure, Properties, and
 Applications. Wiley-VCH; 2007.
This valuable compendium includes chapters from experts working
across a broad spectrum of synthetic and biomolecular foldamer sys-
tems. Contributors evaluate a variety of strategies for directing foldamer
structure and highlight biological applications.
2. Bautista AD, Craig CJ, Harker EA, Schepartz A: Sophistication of
foldamer form and function in vitro and in vivo. Curr Opin Chem
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3. Udugamasooriya DG, Dineen SP, Brekken RA, Kodadek T: A
 peptoid ‘Antibody surrogate’ that antagonizes VEGF receptor
2 activity. J Am Chem Soc 2008, 130:5744-5752.
An innovative cell-based screen is used to identify peptoids capable of
binding selectively to a receptor protein in its membrane context. Five hit
beads are isolated from a 300 000 member library of peptoids on resin.
A dimeric form of one of these hit oligomers is a nanomolar antagonist of
the VEGF receptor 2. Among several groundbreaking aspects of the study
is an in vivo assay of a bioactive peptoid, indicating that the oligomeric
VEGFR2 antagonist is well-tolerated and can inhibit angiogenesis in a
mouse tumor model—auspicious results for ‘peptoid therapy’.
4. Dill KA, Ozkan SB, Shell MS, Weikl TR: The protein folding
problem. Annu Rev Biophys 2008, 37:289-316.
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amide bonds. The propargyl sidechains of the tetramer macrocycle were
subjected to ‘click-chemistry’ conjugation reactions, demonstrating the
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Current Opinion in Chemical Biology 2008, 12:714–721
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Current Opinion in Chemical Biology 2008, 12:714–721
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were obtained of the cyclohexamer and cyclooctamer. The hairpin
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26. Pokorski JK, Jenkins LMM, Feng HQ, Durell SR, Bai YW,
Appella DH: Introduction of a triazole amino acid into a peptoid
oligomer induces turn formation in aqueous solution. Org Lett
2007, 9:2381-2383.
27. Burkoth TS, Beausoleil E, Kaur S, Tang DZ, Cohen FE,
Zuckermann RN: Toward the synthesis of artificial proteins: the
discovery of an amphiphilic helical peptoid assembly. Chem
Biol 2002, 9:647-654.
28. Lee BC, Zuckermann RN, Dill KA: Biomimetic nanostructures:
 creating a high-affinity zinc-binding site in a folded
nonbiological polymer. J Am Chem Soc 2008 doi: 10.1021/
ja802125x. ASAP.
This study describes the first peptoid mimics of metalloproteins. A family
of helical peptoid oligomers are synthesized and conjugated at their
termini through flexible linkers. The presence of thiol and imidazole
groups in the sidechains creates a coordination environment for metal
ions. Certain peptoid sequences bind zinc tightly and selectively, creating
a compact helix–loop–helix assembly, as monitored by FRET.
29. Maayan G, Yoo B, Kirshenbaum K: Heterocyclic amines for the
construction of peptoid oligomers bearing multi-dentate
ligands. Tet Lett 2008, 49:335-338.
30. Fafarman AT, Borbat PP, Freed JH, Kirshenbaum K:
Characterizing the structure and dynamics of folded
oligomers: pulsed ESR studies of peptoid helices. Chem
Commun 2007:377-379.
31. Shin SBY, Kirshenbaum: Conformational rearrangements by
water-soluble peptoid foldamers. Org Lett 2007, 9:5003-5506.
32. Shah NH, Kirshenbaum K: Photoresponsive peptoid oligomers
bearing azobenzene side chains. Org Biomol Chem 2008 doi:
10.1039/b804802a.
33. Kwon YU, Kodadek T: Quantitative evaluation of the relative cell
permeability of peptoids and peptides. J Am Chem Soc 2007,
129:1508-1509.
34. Tan NC, Yu P, Kwon Y-U, Kodadek T: High-throughput
evaluation of relative cell permeability between peptoids and
peptides. Bioorg Med Chem 2008, 16:5835-5861.
35. Wender PA, Mitchell DJ, Pattabiraman K, Pelkey ET, Steinman L,
Rothbard JB: The design, synthesis, and evaluation of
molecules that enable or enhance cellular uptake: peptoid
molecular transporters. Proc Natl Acad Sci U S A 2000,
97:13003-13008.
36. Murphy JE, Uno T, Hamer JD, Cohen FE, Dwarki V,
Zuckermann RN: A combinatorial approach to the discovery of
efficient cationic peptoid reagents for gene delivery. Proc Natl
Acad Sci U S A 1998, 95:1517-1522.
37. Schröder T, Niemeier N, Afonin S, Ulrich AS, Krug HF, Bräse S:
Peptoidic amino- and guanidinium-carrier systems: targeted
drug delivery into the cell cytosol or the nucleus. J Med Chem
2008, 51:376-379.
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38. Utku Y, Dehan E, Ouerfelli O, Piano F, Zuckermann RN, Pagano M,
 Kirshenbaum K: A peptidomimetic siRNA transfection reagent
for highly effective gene silencing. Mol Biosys 2006, 2:312-317.
Cationic peptoids were conjugated to phospholipid headgroups and
used as transfection agents for delivery of RNA oligonucleotides in tissue
culture experiments. These ‘lipitoid’ reagents proved highly effective at
mediating the specific knockdown of target genes. This effect was
observed even in primary cell types that are highly resistant to the action
of typical chemical transfection agents.
39. Xiao XS, Yu P, Lim HS, Sikder D, Kodadek T: A cell-permeable
 synthetic transcription factor mimic. Ang Chem Int Ed 2007,
46:2865-2868.
A peptoid library was screened to identify oligomers capable of binding a
transcriptional co-activator. A peptoid hit sequence was conjugated to a
polyamide to provide specific binding to a targeted region of DNA. The
synthetic construct behaved as a transcription factor mimic and upre-
gulated targeted gene expression. This activity was facilitated by the
favorable membrane permeability characteristics of the peptoid moiety
(as detailed in [33] and [34]).
40. Goodman CM, Choi S, Shandler S, DeGrado WF: Foldamers as
versatile frameworks for the design and evolution of function.
Nat Chem Biol 2007, 3:252-262.
41. Hershberger SJ, Lee SG, Chmiewlewski J: Scaffolds for blocking
protein–protein interactions. Curr Top Med Chem 2007,
7:928-942.
42. Hara T, Durrell SR, Myers MC, Appella DH: Probing the structural
 requirements of peptoids that inhibit HDM2-p53 interactions.
J Am Chem Soc 2006, 128:1995-2004.
A structure-based approach was used to design peptoid sequences
capable of mimicking the presentation of sidechains on a helix of p53
that interact with HDM2 at the protein–protein binding interface. This
study provides valuable analysis on the design of peptoids for antagoniz-
ing protein–protein interactions, an important application of foldamer
research.
43. Lim HS, Archer CT, Kodadek T: Identification of a peptoid
 inhibitor of the proteasome 19S regulatory particle. J Am Chem
Soc 2007, 129:7750-7751.
A 100 000 member library of peptoid heptamers bearing a purine capping
group was synthesized on beads and probed for the ability to bind
proteosomes in a yeast extract. One compound was identified and found
to inhibit the protein unfolding activity of the proteosome in vitro and the
proteolysis activity of the proteosome complex in HeLa cells.
44. Udugamasooriya DG, Dineen SP, Brekken RA, Kodadek T: A
peptoid antagonist of VEGF Receptor 2 recognizes a ‘hotspot’
in the extracellular domain distinct from the hormone-binding
site. Bioorg Med Chem 2008, 16:6338-6343.
45. Wrenn SJ, Weisinger RM, Halpin DR, Harbury PB: Synthetic
 ligands discovered by in vitro selection. J Am Chem Soc 2007,
129:13137-13143.
In a technical tour de force, an evolutionary strategy is established for
amplifying members of a peptoid library in order to discover ligands to a
www.sciencedirect.com
Peptoid architectures Yoo and Kirshenbaum 721
protein target. The synthesis of a library of 108 peptoid oligomers was
encoded by DNA sequences. The physical association of the peptoids
and DNA allowed multiple rounds of selection and amplification. Several
ligands to the protein Crk with Kd values in the micromolar range were
identified. This approach is analogous to phage display, and may enable
the search of vast libraries of synthetic oligomers. The authors suggest it
will be possible to explore libraries including 1013 members. That’s a lot of
peptoids!
46. Chongsiriwatana NP, Patch JA, Czyzewski AM, Dohm MT,
 Ivankin A, Gidalevitz D, Zuckermann RN, Barron AE: Peptoids that
mimic the structure, function, and mechanism of helical
antimicrobial peptides. Proc Natl Acad Sci U S A 2008,
105:2794-2799.
Helical amphiphilic peptoids have been designed to mimic the activity of
natural antimicrobial peptides such as magainin. This study confirms the
activity of these ‘ampetoids’ against a broad range of pathogenic bacteria
and explores the relationship between peptoid structure and function.
Notably, techniques such as specular X-ray reflectivity are used to probe
the interaction of the peptoids with model lipid layers and elucidate their
mechanism of action.
47. Brown NJ, Wu CW, Seurynck-Servoss SL, Barron AE: Effects of
 hydrophobic helix length and side chain chemistry on
biomimicry in peptoid analogues of SP-C. Biochemistry 2008,
47:1808-1818.
A set of helical peptoid oligomers were designed to mimic the structure
and function of the lung surfactant peptide SP-C. The relationship
between secondary structure content and surface activity was evaluated.
These compounds may prove effective replacements for treatment of
respiratory diseases caused by insufficiency of lung surfactant, in parti-
cular for premature infants.
48. Fowler SA, Stacy DM, Blackwell HE: Design and synthesis of
 macrocyclic peptomers as mimics of a quorum sensing signal
from Staphylococcus aureus. Org Lett 2008, 10:2329-2332.
A focused library of cyclic hybrid oligomers including peptide and peptoid
residues were synthesized and evaluated for their ability to mimic macro-
cyclic autoinducing peptides that regulate quorum sensing in S. aureus.
One such ‘peptomer’ was found to stimulate biofilm formation, presum-
ably by inhibiting a protein receptor involved in quorum sensing.
49. Shah NH, Kirshenbaum K: Direct generation of polymer films on
copper surfaces through azide-alkyne cycloaddition reactions
between peptidomimetic oligomers. Macromol Rapid Commun
2008, 29:1134-1139.
50. Statz AR, Barron AE, Messersmith PB: Protein, cell and bacterial
fouling resistance of polypeptoid-modified surfaces: effect of
side-chain chemistry. Soft Matter 2008, 4:131-139.
51. Statz AR, Barron AE, Messersmith PB: New peptidomimetic
polymers for antifouling surfaces. J Am Chem Soc 2005,
127:7922-7927.
52. Combs DJ, Lokey RS: Extended peptoids: a new class of
oligomers based on aromatic building blocks. Tet Lett 2007,
48:2679-2682.
Current Opinion in Chemical Biology 2008, 12:714–721