Tailored Bioorthogonal and Bioconjugate Chemistry: A Source of Inspiration for Developing Kinetic Target-Guided Synthesis Strategies

Kinetic target-guided synthesis (KTGS) is a promising tool for the discovery of biologically active compounds. It relies on the identification of potent ligands that are covalently assembled by the biological targets themselves from a pool of reagents. Significant effort is devoted to developing new KTGS strategies; however, only a handful of biocompatible reactions are available, which may be insufficient to meet the specificities (stability, dynamics, active site topology, etc.) of a wide range of biological targets with therapeutic potential. This Topical Review proposes a retrospective analysis of existing KTGS ligation tools, in terms of their kinetics and analogy with other biocompatible reactions, and provides new clues to expand the KTGS toolkit. By way of examples, a nonexhaustive selection of such chemical ligation tools belonging to different classes of reactions as promising candidate reactions for KTGS are suggested.

Automated summary

Kinetic target-guided synthesis (KTGS) is a promising tool for discovering biologically active compounds by covalently assembling potent ligands from a pool of reagents. However, the current limited number of biocompatible reactions may not meet the specificities of a wide range of biological targets, thus new reaction types are needed.