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((Refimprove|date=May 2011))

'''Peptoids''' (root from the [[Greek language|Greek]] πεπτός, ''peptós'' "digested"; derived from πέσσειν, ''péssein'' "to digest" and the Greek-derived suffix -oid meaning "like, like that of, thing like a ______," ), or poly-''N''-substituted [[glycine]]s, are a class of biochemicals known as biomimetics that replicate the behavior of biological molecules.<ref>((Cite web|title=What if We Could Give Viruses a One-Two Punch? by Berkeley Lab on Exposure|url=https://photostories.lbl.gov/what-if-we-could-give-viruses-a-onetwo-punch|access-date=2021-09-16|website=Exposure|language=en))</ref> [[Peptidomimetic]]s are recognizable by side chains that are appended to the nitrogen atom of the [[peptide]] backbone, rather than to the α-carbons (as they are in [[amino acid]]s). 

==Chemical structure and synthesis==
[[File:Peptoid struc synth.png|frame|text-top|Structure (top) and synthesis (bottom) of peptoids highlighting the submonomer approach.]]
In peptoids, the side chain is connected to the nitrogen of the peptide backbone, instead of the α-carbon as in peptides. Notably, peptoids lack the amide hydrogen which is responsible for many of the [[secondary structure]] elements in peptides and proteins. Peptoids were first invented by Reyna J. Simon, Ronald N. Zuckermann, Paul Bartlett and Daniel V. Santi to mimic protein/peptide products to aid in the discovery of protease-stable small molecule drugs for the East Bay company [[Chiron Corporation|Chiron]].<ref name="pmid1409642">((cite journal | vauthors = Simon RJ, Kania RS, Zuckermann RN, Huebner VD, Jewell DA, Banville S, Ng S, Wang L, Rosenberg S, Marlowe CK | display-authors = 6 | title = Peptoids: a modular approach to drug discovery | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 20 | pages = 9367–9371 | date = October 1992 | pmid = 1409642 | pmc = 50132 | doi = 10.1073/pnas.89.20.9367 | doi-access = free ))</ref><ref>((Cite web|title=What if We Could Give Viruses a One-Two Punch? by Berkeley Lab on Exposure|url=https://photostories.lbl.gov/what-if-we-could-give-viruses-a-onetwo-punch|access-date=2021-09-17|website=Exposure|language=en))</ref>

Following the sub-monomer protocol originally created by Ron Zuckermann,<ref>((cite journal | vauthors =  Zuckermann RN, Kerr JM, Kent SB, Moos WH | title = Efficient method for the preparation of peptoids [oligo(N-substituted glycines)] by submonomer solid-phase synthesis | journal = [[Journal of the American Chemical Society]] | date = 1992 | volume = 114 | issue = 26 | pages = 10646–10647 | doi = 10.1021/ja00052a076))</ref> each residue is installed in two steps: [[acylation]] and displacement. In the acylation step, a haloacetic acid, typically [[bromoacetic acid]] activated by [[diisopropylcarbodiimide]] reacts with the amine of the previous residue. In the displacement step (a classical [[SN2 reaction|S<sub>N</sub>2 reaction]]), an amine displaces the halide to form the ''N''-substituted glycine residue. The submonomer approach allows the use of any commercially available or synthetically accessible amine with great potential for [[combinatorial chemistry]].

==Unique characteristics==
Like D-Peptides and [[Beta-peptide|β peptides]], peptoids are completely resistant to [[proteolysis]],<ref>((cite journal | vauthors = Miller SM, Simon RJ, Ng S, Zuckermann RN, Kerr JM, Moos WH | title = Comparison of the proteolytic susceptibilities of homologous L‐amino acid, D‐amino acid, and N‐substituted glycine peptide and peptoid oligomers. | journal = Drug Development Research | date = May 1995 | volume = 35 | issue = 1 | pages = 20–32 | doi = 10.1002/ddr.430350105 | s2cid = 84619520 ))</ref> and are therefore advantageous for therapeutic applications where proteolysis is a major issue.  Since secondary structure in peptoids does not involve hydrogen bonding, it is not typically [[Denaturation (biochemistry)|denatured]] by solvent, temperature, or chemical denaturants such as [[urea]] (see details below).

Notably, since the amino portion of the amino acid results from the use of any amine, thousands of commercially available amines can be used to generate unprecedented chemical diversity at each position at costs far lower than would be required for similar peptides or peptidomimetics.  To date, at least 230 different amines have been used as side chains in peptoids.<ref name="pmid20714299">((cite journal | vauthors = Culf AS, Ouellette RJ | title = Solid-phase synthesis of N-substituted glycine oligomers (alpha-peptoids) and derivatives | journal = Molecules | volume = 15 | issue = 8 | pages = 5282–5335 | date = August 2010 | pmid = 20714299 | pmc = 6257730 | doi = 10.3390/molecules15085282 | doi-access = free ))</ref>

== Structure ==
Peptoid oligomers are known to be conformationally unstable, due to the flexibility of the main-chain methylene groups and the absence of stabilizing [[hydrogen bond]] interactions along the backbone. Nevertheless, through the choice of appropriate side chains it is possible to form specific steric or electronic interactions that favour the formation of stable secondary structures like helices,<ref name="pmid9539732">((cite journal | vauthors = Kirshenbaum K, Barron AE, Goldsmith RA, Armand P, Bradley EK, Truong KT, Dill KA, Cohen FE, Zuckermann RN | display-authors = 6 | title = Sequence-specific polypeptoids: a diverse family of heteropolymers with stable secondary structure | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 8 | pages = 4303–4308 | date = April 1998 | pmid = 9539732 | pmc = 22484 | doi = 10.1073/pnas.95.8.4303 | doi-access = free ))</ref> especially peptoids with C-α-branched side chains are known to adopt structure analogous to [[polyproline]] I helix.<ref name="pmid9539733">((cite journal | vauthors = Armand P, Kirshenbaum K, Goldsmith RA, Farr-Jones S, Barron AE, Truong KT, Dill KA, Mierke DF, Cohen FE, Zuckermann RN, Bradley EK | display-authors = 6 | title = NMR determination of the major solution conformation of a peptoid pentamer with chiral side chains | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 8 | pages = 4309–4314 | date = April 1998 | pmid = 9539733 | pmc = 22485 | doi = 10.1073/pnas.95.8.4309 | doi-access = free ))</ref> Different strategies have been employed to predict and characterize peptoid secondary structure, with the ultimate goal of developing fully folded peptoid protein structures<ref name="pmid22180903">((cite journal | vauthors = Wetzler M, Barron AE | title = Progress in the de novo design of structured peptoid protein mimics | journal = Biopolymers | volume = 96 | issue = 5 | pages = 556–560 | date = 2011 | pmid = 22180903 | doi = 10.1002/bip.21621 ))</ref>
The cis/trans [[amide bond]] isomerization still leads to a conformational heterogeneity which doesn’t allow for the formation of homogeneous peptoid [[foldamers]].<ref name="pmid18786652">((cite journal | vauthors = Yoo B, Kirshenbaum K | title = Peptoid architectures: elaboration, actuation, and application | journal = Current Opinion in Chemical Biology | volume = 12 | issue = 6 | pages = 714–721 | date = December 2008 | pmid = 18786652 | doi = 10.1016/j.cbpa.2008.08.015 ))</ref>  Nonetheless, scientists were able to find trans-inducer ''N''-Aryl side chains promoting [[polyproline]] type II helix,<ref name="pmid19049458">((cite journal | vauthors = Shah NH, Butterfoss GL, Nguyen K, Yoo B, Bonneau R, Rabenstein DL, Kirshenbaum K | title = Oligo(N-aryl glycines): a new twist on structured peptoids | journal = Journal of the American Chemical Society | volume = 130 | issue = 49 | pages = 16622–16632 | date = December 2008 | pmid = 19049458 | doi = 10.1021/ja804580n ))</ref> and strong cis-inducer such as bulky naphtylethyl<ref name="pmid21861531">((cite journal | vauthors = Stringer JR, Crapster JA, Guzei IA, Blackwell HE | title = Extraordinarily robust polyproline type I peptoid helices generated via the incorporation of α-chiral aromatic N-1-naphthylethyl side chains | journal = Journal of the American Chemical Society | volume = 133 | issue = 39 | pages = 15559–15567 | date = October 2011 | pmid = 21861531 | pmc = 3186054 | doi = 10.1021/ja204755p ))</ref> and tert-butyl<ref name="pmid23590358">((cite journal | vauthors = Roy O, Caumes C, Esvan Y, Didierjean C, Faure S, Taillefumier C | title = The tert-butyl side chain: a powerful means to lock peptoid amide bonds in the cis conformation | journal = Organic Letters | volume = 15 | issue = 9 | pages = 2246–2249 | date = May 2013 | pmid = 23590358 | doi = 10.1021/ol400820y ))</ref> side chains. It was also found that n→π* interactions can modulate the ratio of cis/trans amide bond conformers,<ref name="pmid19860427">((cite journal | vauthors = Gorske BC, Stringer JR, Bastian BL, Fowler SA, Blackwell HE | title = New strategies for the design of folded peptoids revealed by a survey of noncovalent interactions in model systems | journal = Journal of the American Chemical Society | volume = 131 | issue = 45 | pages = 16555–16567 | date = November 2009 | pmid = 19860427 | pmc = 3175426 | doi = 10.1021/ja907184g ))</ref> until reaching a complete control of the cis conformer in the peptoid backbone using a functionalizable triazolium side chain.<ref name="pmid22612307">((cite journal | vauthors = Caumes C, Roy O, Faure S, Taillefumier C | title = The click triazolium peptoid side chain: a strong cis-amide inducer enabling chemical diversity | journal = Journal of the American Chemical Society | volume = 134 | issue = 23 | pages = 9553–9556 | date = June 2012 | pmid = 22612307 | doi = 10.1021/ja302342h ))</ref>

==Applications==
The first demonstration of the use of peptoids was in screening a combinatorial library of diverse peptoids, which yielded novel high-affinity ligands for 7-transmembrane G-protein-couple receptors.<ref name="pmid8064796">((cite journal | vauthors = Zuckermann RN, Martin EJ, Spellmeyer DC, Stauber GB, Shoemaker KR, Kerr JM, Figliozzi GM, Goff DA, Siani MA, Simon RJ | display-authors = 6 | title = Discovery of nanomolar ligands for 7-transmembrane G-protein-coupled receptors from a diverse N-(substituted)glycine peptoid library | journal = Journal of Medicinal Chemistry | volume = 37 | issue = 17 | pages = 2678–2685 | date = August 1994 | pmid = 8064796 | doi = 10.1021/jm00043a007 ))</ref>

Peptoids have been developed as candidates for a range of different biomedical applications,<ref name="pmid19343235">((cite journal | vauthors = Fowler SA, Blackwell HE | title = Structure-function relationships in peptoids: recent advances toward deciphering the structural requirements for biological function | journal = Organic & Biomolecular Chemistry | volume = 7 | issue = 8 | pages = 1508–1524 | date = April 2009 | pmid = 19343235 | pmc = 5962266 | doi = 10.1039/b817980h ))</ref><ref name="pmid19479663">((cite journal | vauthors = Zuckermann RN, Kodadek T | title = Peptoids as potential therapeutics | journal = Current Opinion in Molecular Therapeutics | volume = 11 | issue = 3 | pages = 299–307 | date = June 2009 | pmid = 19479663 | doi =  ))</ref> including antimicrobial agents,<ref name="pmid33807248">((cite journal | vauthors = Diamond G, Molchanova N, Herlan C, Fortkort JA, Lin JS, Figgins E, Bopp N, Ryan LK, Chung D, Adcock RS, Sherman M, Barron AE | display-authors = 6 | title = Potent Antiviral Activity against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids | journal = Pharmaceuticals | volume = 14 | issue = 4 | date = March 2021 | page = 304 | pmid = 33807248 | pmc = 8066833 | doi = 10.3390/ph14040304 | doi-access = free ))</ref> synthetic lung surfactants,<ref name="pmid18834153">((cite journal | vauthors = Brown NJ, Johansson J, Barron AE | title = Biomimicry of surfactant protein C | journal = Accounts of Chemical Research | volume = 41 | issue = 10 | pages = 1409–1417 | date = October 2008 | pmid = 18834153 | pmc = 3270935 | doi = 10.1021/ar800058t ))</ref><ref>((cite journal | vauthors = Czyzewski AM, McCaig LM, Dohm MT, Broering LA, Yao LJ, Brown NJ, Didwania MK, Lin JS, Lewis JF, Veldhuizen R, Barron AE | display-authors = 6 | title = Effective in vivo treatment of acute lung injury with helical, amphipathic peptoid mimics of pulmonary surfactant proteins | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 6795 | date = May 2018 | pmid = 29717157 | pmc = 5931611 | doi = 10.1038/s41598-018-25009-3 ))</ref> ligands for various proteins including Src Homology 3 ([[SH3 domain]]),<ref name="pmid9851931">((cite journal | vauthors = Nguyen JT, Turck CW, Cohen FE, Zuckermann RN, Lim WA | title = Exploiting the basis of proline recognition by SH3 and WW domains: design of N-substituted inhibitors | journal = Science | volume = 282 | issue = 5396 | pages = 2088–2092 | date = December 1998 | pmid = 9851931 | doi = 10.1126/science.282.5396.2088 ))</ref> Vascular Endothelial Growth Factor ([[VEGF]]) receptor 2,<ref name="pmid18386897">((cite journal | vauthors = Udugamasooriya DG, Dineen SP, Brekken RA, Kodadek T | title = A peptoid "antibody surrogate" that antagonizes VEGF receptor 2 activity | journal = Journal of the American Chemical Society | volume = 130 | issue = 17 | pages = 5744–5752 | date = April 2008 | pmid = 18386897 | doi = 10.1021/ja711193x ))</ref> and antibody [[Immunoglobulin G]] biomarkers for the identification of [[Alzheimer's disease]].<ref name="pmid21215375">((cite journal | vauthors = Reddy MM, Wilson R, Wilson J, Connell S, Gocke A, Hynan L, German D, Kodadek T | display-authors = 6 | title = Identification of candidate IgG biomarkers for Alzheimer's disease via combinatorial library screening | journal = Cell | volume = 144 | issue = 1 | pages = 132–142 | date = January 2011 | pmid = 21215375 | pmc = 3066439 | doi = 10.1016/j.cell.2010.11.054 ))</ref>

Due to their advantageous characteristics as described above, peptoids are also being actively developed for use in nanotechnology,<ref name="pmid20383129">((cite journal|display-authors=6|vauthors=Nam KT, Shelby SA, Choi PH, Marciel AB, Chen R, Tan L, Chu TK, Mesch RA, Lee BC, Connolly MD, Kisielowski C, Zuckermann RN|date=May 2010|title=Free-floating ultrathin two-dimensional crystals from sequence-specific peptoid polymers|journal=Nature Materials|volume=9|issue=5|pages=454–460|doi=10.1038/nmat2742|pmid=20383129))</ref> an area in which they may play an important role.<ref name="pmid22180902">((cite journal|author-link=K. Eric Drexler|vauthors=Drexler KE|date=2011|title=Peptoids at the 7th Summit: toward macromolecular systems engineering|journal=Biopolymers|volume=96|issue=5|pages=537–544|doi=10.1002/bip.21623|pmid=22180902|s2cid=36456597))</ref>

=== Antimicrobial agents ===
Researchers supported by grants from the [[National Institutes of Health|NIH]] and [[National Institute of Allergy and Infectious Diseases|NIAID]] tested the efficacy of antimicrobial peptoids against antibiotic-resistant strands of ''[[Mycobacterium tuberculosis]]''.<ref name=":0">((cite journal | vauthors = Kapoor R, Eimerman PR, Hardy JW, Cirillo JD, Contag CH, Barron AE | title = Efficacy of antimicrobial peptoids against Mycobacterium tuberculosis | journal = Antimicrobial Agents and Chemotherapy | volume = 55 | issue = 6 | pages = 3058–3062 | date = June 2011 | pmid = 21464254 | pmc = 3101442 | doi = 10.1128/AAC.01667-10 ))</ref> Antimicrobial peptoids demonstrate a non-specific mechanism of action against the bacterial membrane, one that differs from small-molecule antibiotics that bind to specific receptors (and thus are susceptible to mutations or alterations in bacterial structure). Preliminary results suggested "appreciable activity" against drug-sensitive bacterial strands, leading to a call for more research into the viability of peptoids as a new class of tuberculocidal drugs.<ref name=":0" />

Researchers at the Barron Lab at Stanford University (supported by a [[National Institutes of Health|NIH]] Pioneer Award grant) are currently studying whether upregulation of the human host defense peptide LL-37 or application of antimicrobial treatments based on LL-37 may prevent or treat sporadic Alzheimer’s dementia. Lead researcher Annelise Barron discovered that the innate human defense peptide LL-37 binds to the peptide Ab, which is associated with Alzheimer's disease. Barron's insight is that an imbalance between LL-37 and Ab may be a critical factor affecting AD-associated fibrils and plaques. The project extends focus upon the potential relationship between chronic, oral ''[[P. gingivalis]]'' and herpesvirus (HSV-1) infections to the progression of Alzheimer's dementia.

== See also ==
*[[Peptidomimetic]]
*[[Beta-peptide]]
*[[Peptoid nanosheet|Peptoid Nanosheet]]

== References ==
((Reflist|2))

[[Category:Peptides]]

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