The Clickables

What is Click Chemistry? Selective orthogonal labeling of peptides has been limited by the need to use thiol and amine groups in the target peptide to interact with maleimido, halo-acetyl and NHS-esters of the desired labeling molecule. When more than one thiol or amine is present in a specific peptide, it is difficult to get selective incorporation without using special protecting groups to minimize side reactions. Click chemistry is the popular term that describes a class of efficient and selective reactions that could be used to join molecules together rapidly and in high yield. These groups react - or “click”, achieving high selectivity under mild conditions. The Huisgen 1,3-dipolar cycloaddition,1 in particular the Cu(I)-catalyzed variant, is applied by Meldal2 for the solid phase synthesis of peptidotriazoles, and by Sharpless3 for the creation of covalent links between diverse building blocks. Click chemistry has been used in peptide cyclization, DNA-peptide conjugation, fluorescent dye labeling and surface immobilization of molecules. It has also been used in probing enzyme activities in cell lysates4 or visualizing biomolecules in fixed cells.5,6 Bertozzi7 reported a unique copper-free version of click chemistry to create biomolecular probes for in vivo studies of live mice.

1. Huisgen, 1,3-Dipolar Cycloaddition Chemistry, Vol. 1, (1984) p. 1.
2. Tornoe, et al., J Org Chem, 67, 3057 (2002).
3. Rostovtsev, et al., Angew Chem Int Ed, 41, 2596 (2002).
4. Speers, et al., J Am Chem Soc, 125, 4686 (2003).
5. Beatty, et al., Angew Chem Int Ed, 45, 7364 (2006).
6. Hsu, et al.., Proc Natl Acad Sci USA, 104, 2614 (2007).
7. Baskin, et al., Proc Natl Acad Sci USA, 104, 16793 (2007).

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