Click chemistry is a term coined by Barry Sharpless in 2001 and refers to a set of reactions that are modular, high yielding, and can be performed under mild conditions. They are also selective, easy to perform, and compatible with a wide range of functional groups. Click chemistry has found widespread use in various fields, including drug design. Click chemistry has been used in the development of new drug candidates, drug delivery systems, and imaging agents. In this article, we will discuss some of the applications of click chemistry in drug design.
Bioconjugation
Bioconjugation is a process in which a biomolecule such as a protein or a nucleic acid is attached to a synthetic molecule such as a drug. Click chemistry has been used to develop bioconjugates by coupling the biomolecule with a synthetic molecule through a click reaction. Click chemistry has several advantages over traditional bioconjugation methods, including high efficiency, selectivity, and mild reaction conditions. For example, the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has been used to conjugate a variety of biomolecules including proteins, nucleic acids, carbohydrates, and lipids.
Drug Delivery
Click chemistry has been used in the development of drug delivery systems. One example is the use of click chemistry to conjugate drug molecules to polymers or nanocarriers. The resulting drug conjugates can be used to improve the solubility, stability, and pharmacokinetics of the drug. Click chemistry has been used to conjugate drugs to dendrimers, liposomes, and other nanocarriers. For example, the CuAAC reaction has been used to conjugate doxorubicin to a PEGylated dendrimer, resulting in a drug conjugate with improved stability and anti-tumor activity.
Imaging Agents
Click chemistry has been used to develop imaging agents for use in various imaging modalities such as magnetic resonance imaging (MRI), positron emission tomography (PET), and fluorescence imaging. For example, the CuAAC reaction has been used to conjugate a fluorescent dye to a targeting peptide, resulting in a fluorescent imaging agent with high specificity for cancer cells. Similarly, the CuAAC reaction has been used to conjugate a chelator to a targeting peptide, resulting in a PET imaging agent with high specificity for cancer cells.
Protein Engineering
Click chemistry has been used in protein engineering to introduce new functionalities into proteins. For example, the CuAAC reaction has been used to introduce non-natural amino acids into proteins, resulting in proteins with new properties. Click chemistry has also been used to introduce post-translational modifications into proteins, such as phosphorylation and glycosylation.
Fragment-Based Drug Design
Fragment-based drug design is a strategy for developing new drugs by starting with small, low-affinity compounds called fragments and building them up into high-affinity compounds through iterative optimization. Click chemistry has been used in fragment-based drug design to link fragments together into larger molecules. For example, the CuAAC reaction has been used to link two fragments together to form a new compound with improved affinity for a target protein.
In conclusion, click chemistry has found widespread use in drug design, from bioconjugation to drug delivery and imaging. Click chemistry has several advantages over traditional methods, including high efficiency, selectivity, and mild reaction conditions. Click chemistry has also been used in protein engineering and fragment-based drug design. The versatility of click chemistry makes it a valuable tool for drug design and development.
