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Home » Alkyne-Containing Amino Acids

Alkyne containing amino acids are useful building blocks for preparing modified peptides.  Utilizing Sonogashira coupling or 1,3-cycloaddition with azides, they can form cyclized structures, conjugate with labels or biomolecules, and form structurally diverse amino acid residues.

Sonogashira coupling to propargylglycine (Pra) residues has been used to regioselectively conjugate non-proteinogenic structures to peptides and proteins (H. Dibowski, F.P. Schmidtchen, Angew. Chem. IEE, 1998, 37(4), 476-478).  The reactions were compatible with aqueous solvent systems and independent of other functional groups.  Sonogashira coupling also provided a rapid and efficient route to 18F labeled peptides (J.D. Way, C. Bergman, F. Wuest, Chem. Commun., 2015, 51, 3838-3841).  Copper-free Sonogashira cross-coupling has even been performed in living E. coli cells (J. Li, P.R. Chen, 2012, 13(12), 1728-1731).

Cu(I) catalyzed 1,3-cycloaddition of azides to propargylglycine residues has been employed to link peptides or proteins to a variety of groups (S.S. Gupta, J. Kuzelka, P. Singh, W.G. Lewis, M. Manchester, M.G. Finn, Bioconjugate Chem., 2005, 16(6), 1572-1579), including glycans (D.J. Lee, S.-H. Yang, G.M. Williams, M.A. Brimble, J. Org. Chem., 2012, 77(17)7564-7571), lipids (H.-J. Musiol, S. Dong, M. Kaiser, R. Bausinger, A. Zumbusch, U. Bertsch, L. Moroder, ChemBioChem.,2005, 6(4), 625-628), fluorophores (F. Hu, Y. Huang, G. Zhang, R. Zhao, H. Yang, D. Zhang, Anal. Chem., 2014, 86(15), 7987-7995; M.A. Kamaruddin, P. Ung, M.I. Hossain, B. Jarasrassamee, et al., Bioorg. Med. Chem. Lett., 2011, 21(1), 329-331) and silver nanoparticles (M Gakiya-Teruya, L. Palomino-Marcelo, S. Pierce, A.M. Angeles-Boza, V. Krishna, J.C.F. Rodriguez-Reyes, J. Nanopart. Res., 2020, 22, 90).  Because this “click” reaction is quick, high-yielding and does not generate byproducts, it is a good method of attaching a radioactive label to a peptide or protein.  It was recently utilized, for instance, to attach a 18F-labeled glycan to a peptide for use as an imaging probe in positron emission tomography (S. Maschauer, J. Einsiedel, R. Haubner, C. Hecke, M. Ocker, H. Hübner, et al., Angew. Chem. IEE, 2010, 49(5), 976-979).

Alkyne-containing amino acids such as propargylglycine have been used to form cyclic peptides by 1,3-cycloaddition reaction with azide-containing amino acids.  A conformationally constrained cyclic peptide inhibitor of STAT3 was formed by the Cu(I) catalyzed “click” reaction of azidonorleucine and propargylglycine residues in a linear precursor (J. Chen, Z. Nikolovska-Coleska, C.-Y. Yang, C. Gomez, W. Gao, et al, Bioorg. Med. Chem. Lett., 2007, 17(14), 3939-3942). Cyclic analogs of α-MSH (M.E. Martin, M.S. O’Dorisio, W.M. Leverich, K.C. Kloepping, S.A. Walsh, M.K. Schultz, 2013, In: Baum, R; Rösch, F (eds), Theranostics, Gallium-68, and Other Radionucleotides. Recent Results in Cancer Resaerch, vol. 194, Springer, Berlin) and NGR/RGD peptide (B.B. Metaferia, M. Ritter, J.S. Gheeya, A. Lee, H. Hempel, et al., Bioorg. Med. Chem. Lett., 2010, 20(24), 7337-7340) have been prepared in this way.

Alkynyl- and azide-containing amino acids have been utilized to prepare stapled peptides.  Stapled peptides are a special type of cyclized peptide where the cyclic structure links near-by loops of an alpha helix.  The linking structure, called the staple, stabilizes the helix and helps hold the peptide in this conformation.  In many of the recently reported stapled peptides, the staple was formed by ring-closing metathesis between two terminal alkenes.  This chemistry is sometimes difficult and the required catalyst is expensive.  Stapling by Cu(I) catalyzed click chemistry, however, is usually easy and the catalyst is inexpensive.

Click chemistry stapling in parathyroid hormone-related protein (11-19) has been studied.  An i, i+4 staple with 5 or 6 methylene groups stabilized the helical structure and closely reproduced the the helical structure stabilized by a Lys13-Asp17 lactam. (M. Scrima, A. Le Chevalier-Isaad, P. Rovero, et al., Eur. J.Org. Chem., 2010, (3), 446-457).  A little later, another group studied stapling of BCL9 (351-379). They investigated the effects of the stereochemistry of the staple components had on helix stabilization and activity.  They found that replacing 360Glu with Lys(N3) and 364Gln with either L-Pra or D-Pra, then forming the 1,4-substituted triazole provided peptides with enhanced helicity.  The peptide with the Lys(N3)-D-Pra staple displayed greater activity than the peptide with the staple formed with L-Pra (S.A. Kawamoto, A. Coleska, X. Ran, et al., J. Med. Chem. 2012, 55(3), 1137-1146).  Subsequently, they developed a click-stapled peptide to block protein-protein interaction between RAP1 and TFR2 in the shelterin complex (X. Ran, L. Liu, C.-Y. Yang, et al., J. Med.Chem. 2016, 59(1), 328-334).  An additional demonstration of i, i+4 click stapling between Lys(N3) and Pra residues was reported in polybia-MP1, a peptide from the venom of Brazilian wasp Polybia paulista which displays broad spectrum antibacterial activity without hemolytic or cytotoxic activity.  The stapled product displayed sustained antibacterial activity and enhanced trypsin resistance (B. Liu, W. Zhang, S. Gou, et al. J. Pept. Sci. 2017, 23(11), 824-832). These results demonstrate that Lys(N3)-Pra click stapled peptides can be potential pharmaceutical leads.