When it comes to the natural world, humanity has extreme difficulty imitating organic processes. From spider silk to bird flight, natural processes, while understood, can be near impossible to produce with human technology. The generation of organic molecules remained such a struggle, up until the foundational development of bioorthogonal click chemistry: a class of simple, efficient reactions used to produce complex biological compounds.
Contrary to what one may think, some of the most complex molecules in the world are found in nature. These organic compounds are almost entirely made of carbon and hydrogen linking together to form intricate structures. Even so, they’re extremely difficult to replicate in a lab setting, requiring dozens of steps and producing exorbitant amounts of waste due to the reluctance of carbon to react with itself, (McVean, 2022), as demonstrated in Figure 1. Regardless, these molecules were essential to the production of medications, biotechnologies, and agrichemicals, dictating the need for their synthesis (ACS, 2023).
In 2001, Dr. Barry Sharpless decided to challenge the inanity of biological compound synthesis procedures. He introduced the idea of linking preformed carbon structures together with more reactive elements such as nitrogen, calling it click chemistry (Kolb, Finn and Sharpless, 2001). Click chemistry would use high yielding reactions to “click” carbon-based molecules together, forming stable yet elaborate structures. Fascinatingly, he found that as few as the 35 most common carbon-based compounds could be used to create nearly infinite molecules (McVean, 2022). The process is similar to using inconspicuous individual LEGO® blocks to build huge, complicated structures. For example, LEGO® Millennium Falcon, anyone?
To join compounds together, the two most notable “click” reactions are copper-catalyzed azide-alkyne cycloaddition (CuAAC) (Figure 2) and strain-promoted azide-alkyne cycloaddition (SPAAC) (Ian Chio & Bane, 2020). The CuAAC reaction, pioneered by Dr. Morton Meldal, uses the energy of a copper catalyst to “click” biomolecules together (The Royal Swedish Academy of Sciences, 2022). However, the toxicity associated with copper limits its biological applications. In 2004, Dr. Carolyn Bertozzi addressed this issue by introducing bioorthogonal click chemistry, eliminating the need for copper in discovering that she could instead harness the potential energy of strained molecules to “click” compounds (Agard, Prescher and Bertozzi, 2004). With SPAAC, the applicability of click chemistry in living systems skyrocketed. In fact, click chemistry’s momentous discovery earned Dr. Barry Sharpless, Dr. Morton Meldal, and Dr. Carolyn Bertozzi the 2022 Nobel Prize in Chemistry (The Royal Swedish Academy of Sciences, 2022).
One use of particular interest is click chemistry’s application to cancer therapy. For example, mesenchymal stem cells (MSCs) have been proposed as a vehicle for cancer drug delivery directly to tumor sites as an alternative to non-specific treatment options such as chemotherapy (Takayama, Kusamori and Nishikawa, 2019). Traditional methods of loading MSCs with drugs via endocytosis require lots of time and limited efficacy. Alternatively, bioorthogonal click chemistry could be employed to “click” drug nanoparticles to the MSCs more effectively.
Presently, bioorthogonal click chemistry has emerged as a game-changer in the realm of drug development. Its optimization of pharmacokinetics, production, and delivery of drugs have propelled it to the forefront of modern biochemistry (Kondengadan, et al., 2023). Thanks to click chemistry, the future holds exciting possibilities for the development of safer, more efficacious drugs to address the diverse health challenges facing humanity today.
References
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Agard, N.J., Prescher, J.A. and Bertozzi, C.R., 2004. A strain-promoted [3 + 2] azide−alkyne cycloaddition for covalent modification of biomolecules in living systems. Journal of the American Chemical Society, 126(46), pp.15046–15047. https://doi.org/10.1021/ja044996f
Ian Chio, T. and Bane, S.L., 2019. Click chemistry conjugations. Methods in Molecular Biology, pp.83–97. https://doi.org/10.1007%2F978-1-4939-9929-3_6
Kolb, H.C., Finn, M.G. and Sharpless, K.B., 2001. Click chemistry: Diverse chemical function from a few good reactions. ChemInform, 32(35). https://doi.org/10.1002/1521-3773(20010601)40:11%3C2004::aid-anie2004%3E3.0.co;2-5
Kondengadan, S.M., Bansal, S., Yang, C., Liu, D., Fultz, Z. and Wang, B., 2023. Click chemistry and drug delivery: A bird’s-eye view. Acta Pharmaceutica Sinica B, 13(5), pp.1990–2016. https://doi.org/10.1016/j.apsb.2022.10.015
McVean, A., 2022. A lesson from nature: What click chemistry is, and why it won a Nobel prize. [online] Office for Science and Society. Available at: <https://www.mcgill.ca/oss/article/medical-did-you-know/lesson-nature-what-click-chemistry-and-why-it-won-nobel-prize> [Accessed 10 Nov. 2023].
Reusch, W., 1970. Principles of Organic Synthesis. [online] Synthesis. Available at: <https://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/synth2.htm> [Accessed 10 Nov. 2023].
The Royal Swedish Academy of Sciences, 2022. Their functional chemistry works wonders. [PDF] Stockholm: The Royal Swedish Academy of Sciences. Available at: https://www.nobelprize.org/uploads/2022/10/popular-chemistryprize2022-2.pdf [Accessed 10 Nov. 2023].
Takayama, Y., Kusamori, K. and Nishikawa, M., 2019. Click chemistry as a tool for cell engineering and drug delivery. Molecules, 24(1), p.172. https://doi.org/10.3390/molecules24010172