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Home » Azide and Alkyne-Containing Amino Acids

Azide and alkyne containing amino acids are useful building blocks for incorporating “click chemistry” into peptide synthesis.  The copper(I) catalyzed 1,3-dipolar cycloaddition of azides with alkynes to form 1,4-substituted 1,2,3-triazoles is a convenient method for forming cyclic peptides, attaching labels to peptides, and conjugating peptides with other biomolecules.  Advantages of this click reaction are high yields, no by-products, simple purification, and it can be performed in aqueous solvents.  This copper(I) catalyzed cycloaddition produces triazole products are exclusively 1,4-substituted.  Later it was discovered that using a ruthenium catalyst produced the 1,5-regioisomer. 

One application of azide and alkyne-containing amino acids in peptide synthesis is to replace disulfide bonds.  In the antimicrobial peptide tachyplesin-1, replacement of both disulfide bonds with 1,4-substituted triazoles generated analogs that had similar or slightly better activity than the native peptide (K. Holland-Nell, M. Meldal, Angew. Chem. Int. Ed. Engl., 2011, 50, 5204-5406). The triazole bridges were formed by reaction of propargylglycine (Pra) residues with 2-Abu(N3) or Nva(N3) residues.  In the case of the monocyclic sunflower trypsin inhibitor-I, the 1,5-substituted triazole produced by ruthenium-catalyzed cyclization had the same activity while the 1,4-substituted regioisomer was less active (M. Empting, O. Avrutina, R. Meusinger, S. Fabritz, et al., Angew. Chem. Int. Ed. Engl. 2011, 50, 5207-5211).

Another application of azide and alkyne-containing amino acids is in side-chain-to-side-chain cyclization (A. Le Chavalier Isard, A.M. Panini, M. Chirer, P. Rovero, J. Pept. Sci., 2009, 15, 451-454).  This provides an alternative to the ring-closing-metathesis reaction in preparing stapled peptides (V.H. Lau, Y. Wu, P. deAndrade, W.R.J.D. Galloway, D.R. Spring, Nat. Protoc., 2015, 10, 585-594).

The Cu(I) catalyzed click reaction between azides and alkynes is a quick, reliable method of linking peptides with fluorescent dyes, isotopic and radioactive tags, and other biomolecules such as glycans, proteins, and nucleic acids (A. A. H. Ahmad Fuaad, F. Azmi, M. Skwarczynski, I. Toth, Molecules, 2013, 18, 13148-13174).