Surprising behavior of NXO-peptides

NXO building blocks are modified amino acids where the N-terminus is converted into an acid by the use of oxalic acid and the C-terminus as hydrazide forms a free amine. By this double conversion, both the C- and the N-terminus of any amino acid are being inverted, while the original stereochemical conformation at the chiral carbon is maintained.

Properties of NXO peptides:

• amino acids with inverted N and C terminus;
• available as building blocks for standard Fmoc/tBu protocols in solution and solid phase synthesis;
• available on custom synthesis basis for all canonical and unusual amino acids;
• bearing the same hydrogen bond donor and acceptor properties as a tripeptide in one single building block;
• ideal for the specific design of beta-sheets and beta-turns in peptidomimetics.

It is a significant property of peptides that this combined oxalo-retro azapeptide has the same donor and acceptor distances and properties for hydrogen bridge formation as a tripeptide fragment and therefore induces beta-sheet formation at this position and well defined beta- sheet dimers.

Any NXO building block can easily be introduced by a single standard coupling protocol and replaces in one step a tripeptide moiety.

References:

• NXO Building Blocks for Backbone Modification of Peptides and Preparation of Pseudopeptides; C. Rabong, U. Jordis and J. B. Phopase; J Org Chem 2010; 75: 2492-2500. doi:10.1021/jo902518r
• Surprising behavior of NXO-peptides toward the lithium hydroxide solvolysis; F. A. Khan, C. Rabong, U. Jordis and J. Phopase; Tetrahedron Lett 2013; 54: 3679-3682. doi:10.1016/j.tetlet.2013.05.010
• Templates That Induce .alpha.-Helical, .beta.-Sheet, and Loop Conformations; J. P. Schneider and J. W. Kelly; Chem Rev 1995; 95: 2169-2187. doi:10.1021/cr00038a015
• Between the Sheets: Why Do Protein Strands Line Up?; R. F. Service; Science 1996; 274: 34-35. doi:10.1126/science.274.5284.34
• The 2.2 A crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with RaplA and a GTP analogue; N. Nassar, G. Horn, C. A. Herrmann, A. Scherer, F. McCormick and A. Wittinghofer; Nature 1995; 375: 554-560. doi:10.1038/375554a0
• Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ; D. A. Doyle, A. Lee, J. Lewis, E. Kim, M. Sheng and R. MacKinnon; Cell 1996; 85: 1067-76. doi:10.1016/S0092-8674(00)81307-0
• Design and synthesis of a β-strand inducer Application to ICAM-1/LFA-1 mediated cellular adhesion; W. F. Michne and J. D. Schroeder; Int J Pept Protein Res 1996; 47: 2-8. doi:10.1111/j.1399- 3011.1996.tb00803
• Asymmetric synthesis of two-residue modules designed for mimicry of beta strands; J. C. Roberts, P. V. Pallai and J. Rebek Jr; Tetrahedron Lett 1995; 36: 691-694. doi:http://dx.doi.org/10.1016/0040- 4039(94)02354-E
• Design and synthesis of peptidomimetic inhibitors of HIV-1 protease and renin. Evidence for improved transport; A. B. Smith, R. Hirschmann, A. Pasternak, R. Akaishi, M. C. Guzman, D. R. Jones, T. P. Keenan, P. A. Sprengeler and P. L. Darke; J Med Chem 1994; 37: 215-218. doi:10.1021/jm00028a001
• Targeting the Dimerization Interface of HIV-1 Protease: Inhibition with Cross-Linked Interfacial Peptides; R. Zutshi, J. Franciskovich, M. Shultz, B. Schweitzer, P. Bishop, M. Wilson and J. Chmielewski; J Am Chem Soc 1997; 119: 4841-4845. doi:10.1021/ja962496j
• Crystal structure of the met represser-operator complex at 2.8 [angst] resolution reveals DNA recognition by [beta]-strands; W. S. Somers and S. E. V. Phillips; Nature 1992; 359: 387-393. doi:10.1038/359387a0
• Alzheimer's disease: a central role for amyloid; D. J. Selkoe; J Neuropathol Exp Neurol 1994; 53: 438-47
• A Reductionist View of Alzheimer's Disease; P. T. Lansbury; Accounts of chemical research 1996; 29: 317- 321. doi:10.1021/ar950159u
• Synthesis and conformational analysis of epindolidione-derived peptide models for .beta.-sheet formation; D. S. Kemp, B. R. Bowen and C. C. Muendel; J Org Chem 1990; 55: 4650-4657. doi:10.1021/jo00302a033
• Highly ordered structures of peptides by using molecular scaffolds; T. Moriuchi and T. Hirao; Chemical Society Reviews 2004; 33: 294-301. doi:10.1039/b307632f
• Model systems for β-hairpins and β-sheets; R. M. Hughes and M. L. Waters; Current Opinion in Structural Biology 2006; 16: 514-524. doi:http://dx.doi.org/10.1016/j.sbi.2006.06.008
• Conformational Analysis of β-Turn Structure in Tetrapeptides Containing Proline or Proline Analogs; T. Hayashi, T. Asai and H. Ogoshi; Tetrahedron Lett 1997; 38: 3039-3042. doi:http://dx.doi.org/10.1016/S0040-4039(97)00529-7
• Synthesis and conformational analysis of a type VIb [small beta]-turn mimetic based on an eight- membered lactam; S. Derrer, J. E. Davies and A. B. Holmes; Journal of the Chemical Society, Perkin Transactions 1 2000: 2957-2967. doi:10.1039/b003791p
• Torsion angle based design of peptidomimetics: A dipeptidic template adopting β-I Turn (Ac-Aib-AzGly– NH2); S. Ro, H.-J. Lee, I.-A. Ahn, D.-K. Shin, K.-B. Lee, C.-J. Yoon and Y.-S. Choi; Bioorganic & Medicinal Chemistry 2001; 9: 1837-1841. doi:http://dx.doi.org/10.1016/S0968-0896(01)00094-3