“Click” chemistry, as its name suggests, refers to a class of reactions that efficiently and selectively join molecules together. These reactions are valuable for their speed, reliability, and ability to produce few byproducts, making them ideal for drug development and biomaterials. A key advantage of click chemistry is bioorthogonality – functional groups specifically react with each other while remaining inert to biological systems. This enables precise modification of biomolecules, surfaces, polymers, and nanomaterials without disrupting sensitive structures.
K. Barry Sharpless and colleagues won the 2022 Nobel Prize in Chemistry for their work developing click chemistry in 2001. Sharpless defined click chemistry as a group of reactions that “must be modular, wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by nonchromatographic methods, and be stereospecific.” In other words, click chemistry can be conducted in mild conditions, is high yield, and has minimal byproduct formation.
The most widely used click chemistry reaction is the copper-catalyzed azide–alkyne cycloaddition (CuAAC), in which an azide reacts with a terminal alkyne in the presence of copper(I) to form a stable 1,2,3-triazole linkage. This reaction is considered the benchmark of click chemistry because of its high yields, exceptional selectivity, fast reaction rates, and compatibility with mild, water-containing conditions. In this dosage, however, copper is toxic to living cells.
While CuAAC dominates in general laboratory and industrial use, copper-free variants such as strain-promoted azide–alkyne cycloaddition (SPAAC) are often preferred for biological applications where copper toxicity is a concern.
The following are some common applications of click chemistry:
- Bioconjugation
What is bioconjugation? Bioconjugation involves creation of a covalent bond between two molecules, at least one of which is a biomolecule (enzyme, antibody). By harnessing the precision of the biomolecule, researchers can target specific areas of the body with drugs and medicines.
Click chemistry allow precise attachment of drugs, fluorophores, peptides, and polymers to antibodies, nucleic acids, and nanoparticles, supporting the development of antibody-drug conjugates (ADCs), diagnostic probes, and other targeted therapies. For instance, rhodamine, a fluorophore, can be linked rapidly to norbenene and tetrazine for imaging and labeling applications.
2. Drug Delivery
Click chemistry is used to construct PEGylated systems, hydrogels, and functionalized surfaces with controlled architecture and stability. Smart delivery chemistry focuses on the construction of functional systems that transport and release therapeutic or bioactive agents with precision and control. From preclinical research to translational medicine, click-enabled delivery platforms are a foundation of modern drug delivery and biomaterials engineering.
Click reagents have been used in a variety of approved therapies, most notably in several ADCs now approved for cancers including lymphoma, breast cancer, and cervical cancer. PEGylated drugs have also been approved for diseases such as Hepatitis B and C and autoimmune diseases such as Crohn’s and rheumatoid arthritis.
3. Materials Chemistry and Surface Modification
Advanced materials chemistry uses click reactions to construct polymers, networks, coatings, and nanostructured materials with precise control over composition and functionality. Surface engineering chemistry involves the modification of material interfaces to introduce specific chemical, biological, or physical properties. The modular nature of click chemistry enables rapid synthesis of functional polymers, crosslinked systems, and hybrid materials with tailored mechanical, chemical, or biological properties. Because click reactions are efficient and produce minimal side reactions, they enable uniform surface coverage and robust attachment of biomolecules, polymers, or signaling moieties. These tools are essential for creating high-performance interfaces in medical and analytical devices and advanced sensing platforms.
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References:
Devaraj, N. K., & Finn, M. G. (2021). Introduction: click chemistry. Chemical Reviews, 121(12), 6697-6698.
Devaraj, N. K., Weissleder, R., & Hilderbrand, S. A. (2008). Tetrazine-based cycloadditions: application to pretargeted live cell imaging. Bioconjugate chemistry, 19(12), 2297-2299.
Hein, C. D., Liu, X. M., & Wang, D. (2008). Click chemistry, a powerful tool for pharmaceutical sciences. Pharmaceutical research, 25(10), 2216-2230.
Kaur, J., Saxena, M., & Rishi, N. (2021). An overview of recent advances in biomedical applications of click chemistry. Bioconjugate chemistry, 32(8), 1455-1471.