Bioconjugation

Bioconjugation is a chemical strategy to form a stable covalent link between two molecules, at least one of which is a biomolecule.

Recent advances in the understanding of biomolecules enabled their application to numerous fields like medicine and materials. Synthetically modified biomolecules can have diverse functionalities, such as tracking cellular events, revealing enzyme function, determining protein biodistribution, imaging specific biomarkers, and delivering drugs to targeted cells. Bioconjugation is a crucial strategy that links these modified biomolecules with different substrates.

Synthesis of bioconjugates involves a variety of challenges, ranging from the simple and nonspecific use of a fluorescent dye marker to the complex design of antibody drug conjugates. As a result, various bioconjugation reactions – chemical reactions connecting two biomolecules together – have been developed to chemically modify proteins. Common types of bioconjugation reactions are coupling of lysine amino acid residues, coupling of cysteine residues, coupling of tyrosine residues, modification of tryptophan residues, and modification of the N- and C- terminus.

However, these reactions often lack chemoselectivity and efficiency, because they depend on the presence of native amino acid residues, which are usually present in large quantities that hinder selectivity. There is an increasing need for chemical strategies that can effectively attach synthetic molecules site specifically to proteins. One strategy is to first install a unique functional group onto a protein, and then a bioorthogonal or click type reaction is used to couple a biomolecule with this unique functional group. The bioorthogonal reactions targeting non-native functional groups are widely used in bioconjugation chemistry. Some important reactions are modification of ketone and aldehydes, Staudinger ligation with azides, copper-catalyzed huisgen cyclization of azide, strain promoted huisgen cyclization of azide.

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