Ligand tricks for faster clicks: bioconjugation via the CuAAC reaction

The chemical modification of biological systems has become increasingly common. One of the most widely used methods in this area is click chemistry, which has gained significant attention over the past twenty years. Bioorthogonal reactions, first introduced by Bertozzi, are closely related to click reactions in biological systems. Among various click reactions, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) is especially important. Although CuAAC offers many advantages in bioorthogonal reactions, the copper catalyst can cause problems, as it may be toxic in biological settings. Researchers have worked hard to solve this issue by using reducing agents and a variety of coordinating ligands to reduce copper's toxic effects. In this review, we discuss the benefits and limitations of CuAAC click reactions. The main goal is to give a thorough overview of new methods developed by scientists to reduce copper's harmful effects in CuAAC reactions within biological systems.