In a remarkable advancement in the field of Chemistry, three eminent scientists were awarded the 2022 Nobel Prize. The renowned trio – Carolyn R Bertozzi, Morten Meldal, and K Barry Sharpless- have made significant contributions to the development of Click Chemistry and Bioorthogonal Chemistry. While Sharpless is a second-time laureate, having won the award earlier for creating ‘click chemistry’, Meldal is recognised for independently introducing the ‘triazole’ chemical structure. Bertozzi, on her part, made strides in developing bioorthogonal reactions that function within living organisms.
The Genesis of Click Chemistry
Conceived by Barry Sharpless around 2000, Click Chemistry is an innovative approach to molecular bonding where smaller molecules with complete carbon frameworks are juxtaposed for simpler, efficient reactions. It moves away from conventional chemistry that relies on forcing carbon atoms to bond. Instead, it aims at selecting simple molecule interactions that harbour a strong intrinsic drive towards bonding, resulting in quicker, less wasteful processes.
This minimalist chemistry has significant implications in medical applications, particularly in combating cellular pathogens, even though it doesn’t replicate natural molecules perfectly.
Azide-Alkyne Cycloaddition: A Giant Leap
Meldal and Sharpless independently introduced the copper-catalysed azide-alkyne cycloaddition- the jewel in the crown of Click Chemistry during the 2000s. Meldal was the pioneer in discovering that adding copper ions to a reaction between an alkyne and an acyl halide resulted in a triazole. This ring-like stable chemical structure is a common element in pharmaceuticals, dyes, and agricultural chemicals. The valuable addition of copper ions allowed better control of the reaction, creating a solitary substance.
Besides, azide, an N3 organic compound and alkyne, a hydrocarbon with at least one carbon-carbon triple bond together, form the triazole. This simple and effective chemical reaction has extensive applications in drug development, DNA mapping, and creating improved materials.
Bioorthogonal Reactions: Taking Chemistry Inside Living Organisms
Bioorthogonal reactions, an innovation by Bertozzi, operate within living organisms without causing any disruptions to normal cellular chemistry. When combined with nanotechnology, these reactions can revolutionize biomedicine in diverse areas such as molecular bioimaging, targeted delivery, in situ drug activation, study of cell–nanomaterial interactions, biosensing, etc.
In particular, using bioorthogonal reactions, researchers have significantly enhanced the targeting accuracy of cancer pharmaceuticals.
Developing Cancer Fighting Click Chemistry: Spotting Glycans
Bertozzi endeavored to attach fluorescent molecules to glycans, a type of elusive carbohydrate found on the surface of cells essential to the immune system. To achieve this, Bertozzi adopted the same azide as used by Sharpless and Meldal. The azide not only avoids interaction with other cell parts but is also safe to use in living beings.
In 2004, Bertozzi developed an alternate click chemistry reaction that operated without toxic copper, making it safe for living cells. Today, her work is instrumental in identifying glycans on tumour cells’ surface and blocking their defensive systems that can incapacitate immune cells. Currently, clinical trials are underway for people with advanced cancer, and researchers have begun developing “clickable antibodies” that track tumours and deliver radiation doses accurately to cancer cells.