The chemical modification of amino acid side chains dates back over 100 years, and today a range of bioconjugation reactions are used routinely to change the properties of proteins as dictated by the application or analysis method at hand. Owing to developments in the characterization of protein bioconjugates by mass spectrometry and high- field NMR, a substantially increased set of protein modification reactions has recently become available. As we know, protein mediate virtually every cellular process. They are involved with transcription, translation, transport, cell cycle control, the determination of cell type and function, protein folding, post-translational modifications, signal transduction, metabolism and energy production, cell structure and motility, the formation of biological machines, cell and organism defense, and apoptosis. The protein bioconjugation technology allows new protein targets to be addressed, leading to advances in biological understanding, new protein-drug conjugates, targeted medical imaging agents and hybrid materials with complex functions.
Fig.1 Examples of protein conjugation
Conjugation with artificial nucleic acids allows proteins to be modified with a synthetically accessible, robust tag. DNA-protein conjugates have been assembled into model systems for the investigation of catalytic cascade reactions and light-harvesting devices. Such hybrid conjugates are also used for the biofunctionalization of planar surfaces for microarrays and nanoarrays, and for decorating inorganic nanoparticles to enable applications in sensing, materials science, and catalysis.
Peptides can be specifically attached to proteins via their N or C termini through tyrosine bioconjugation using a three-component Mannich-type strategy. Conjugation with peptides enhances protection against enzymatic hydrolysis. Single-step and site-specific conjugation of bioactive peptides to proteins can be achieved via a self-contained succinimidyl bis-arylhydrazone, allowing formation of bioconjugates used for vaccines or mechanistic studies.
The conjugation of site-specific polyethylene glycol (PEG) and proteins can extend the serum half-life and stability/solubility of protein. Polymer-protein conjugation has expanded to include scaffolds for drug delivery, tissue engineering, and microbial inhibitors. For example, human growth hormone and PEG conjugates have excellent pharmacokinetics, minimal loss of biological activity, and no apparent immunogenicity in vivo. The specific conjugation of a synthetic polymer to a protein conveys its physico-chemical properties and, therefore, modifies the biodistribution and solubility of the protein, making it in certain cases soluble and active in organic solvents.
Antibody-drug conjugates, one of toxin or small molecules -protein conjugates, preferentially deliver cytotoxic drugs to cells presenting tumor-associated antigens to achieve improved drug efficacy and safety. We can synthesize various antibody-drug conjugates such as kinase inhibitors, nuclear hormone receptor agonists, HDAC inhibitors, which can improve therapeutic index and better pharmacokinetic properties in rodents.
Protein can also be conjugated to other molecules such as fluorescent dyes, carbohydrate, self or other protein, other spectroscopic probes. For example, fluorescent dyes can be conjugated both in vitro, such as for FRET experiments to study protein dynamics and in vivo for specific labeling on cell surfaces. Spin labels also have been conjugated to probe protein structure by electron paramagnetic. Carbohydrate-protein conjugates can be used in cancer vaccines and bacterial vaccines and can be synthesized via reductive amination using sodium cyanoborohydride reagent.
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