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Peptoids, or poly-N-substituted glycines, are a class of peptidomimetics whose side chains are appended to the nitrogen atom of the peptide backbone, rather than to the α-carbons (as they are in amino acids).
Chemical structure and synthesis
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, Paul Bartlett and Daniel V. Santi to mimic protein/peptide products to aid in the discovery of protease-stable small molecule drugs.
Following the sub-monomer protocol originally created by Ron Zuckermann, 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), 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.
Like D-Peptides and β peptides peptoids are completely resistant to proteolysis, 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 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.
Peptoids with alpha-chiral bulky side chains are known to adopt a Polyproline-type I-like conformation. Unlike regular proteins, this structure is stable in different organic solvents, temperatures up to 75 degrees Celsius, denaturants such as 8M urea, and different ionic strengths. Different strategies have been employed to predict and characterize peptoid secondary structure, with an ultimate goal of developing fully folded peptoid protein structures.
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.
Peptoids have been developed as candidates for a range of different biomedical applications, including antimicrobial agents and synthetic lung surfactants, as well as ligands for various proteins including Src Homology 3 (SH3 domain), Vascular Endothelial Growth Factor (VEGF) receptor 2, and antibody Immunoglobulin G biomarkers for the identification of Alzheimer's disease.
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- Reyna J Simon, Paul A Bartlett, Daniel V Santi, "Peptoid Mixtures", US Patent 5,811,387, Sept 22, 1998
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- Adrian S. Culf and Rodney J. Ouellette, Solid-Phase Synthesis of N-Substituted Glycine Oligomers (α-Peptoids) and Derivatives Molecules (2010), 15, 5282-5335 doi:10.3390/molecules15085282
- Philippe Armand, Kent Kirshenbaum, Richard A. Goldsmith, Shauna Farr-Jones, Annelise E. Barron, Kiet T. V. Truong, Ken A. Dill, Dale F. Mierke, Fred E. Cohen, Ronald N. Zuckermann, and Erin K. Bradley, "NMR determination of the major solution conformation of a peptoid pentamer with chiral side chains", Proceedings of the National Academy of Sciences (95(8)): 4309–4314
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- Sarah A. Fowler, Helen E. Blackwell, Structure-function relationships in peptoids: recent advances toward deciphering the structural requirements for biological function, Org. Biomol. Chem. (2009), 7(8), 1508-1524 doi:10.1039/B817980H
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- Jack T. Nguyen, Christoph W. Turck, Fred E. Cohen, Ronald N. Zuckermann, Wendell A. Lim, Exploiting the basis of proline recognition by SH3 and WW domains: design of N-substituted inhibitors, Science (1998), 282(5396), 2088-2092 doi:10.1126/science.282.5396.2088
- D. Gomika Udugamasooriya, Sean P. Dineen, Rolf A. Brekken and Thomas Kodadek, A Peptoid "Antibody Surrogate” That Antagonizes VEGF Receptor 2 Activity and the proteosome regulatory particle, Journal of the American Chemical Society, (2008), 130(17), 5744-5752, doi:10.1021/ja711193x
- M. Muralidhar Reddy, Rosemary Wilson, Johnie Wilson, Steven Connell, Anne Gocke, Linda Hynan, Dwight German, Thomas Kodadek, Identification of candidate IgG biomarkers for Alzheimer's disease via combinatorial library screening, Cell (2011), 144(1), 132-142 doi:10.1016/j.cell.2010.11.054 PMID 21215375
- Ki Tae Nam, Sarah A. Shelby, Philip H. Choi, Amanda B. Marciel, Ritchie Chen, Li Tan, Tammy K. Chu, Ryan A. Mesch, Byoung-Chul Lee, Michael D. Connolly, Christian Kisielowski, Ronald N. Zuckermann Free-floating ultrathin two-dimensional crystals from sequence-specific peptoid polymers, Nat. Mater. (2010), 9(5), 464-460 doi:10.1038/nmat2742
- K. Eric Drexler, Peptoids at the 7th summit: Toward macromolecular systems engineering Biopolym. Pept. Sci. (2011)doi:10.1002/bip.21623