title: New insights into the kinetic target-guided synthesis of protein ligands.
abstract: The kinetic target-guided synthesis (KTGS) strategy is an unconventional discovery approach that takes advantage of the presence of the biological target itself in order to irreversibly assemble the best inhibitors from an array of building blocks. This strategy has grown over the last two decades notably after the introduction of the in situ click chemistry concept by Sharpless and colleagues in the early 2000s based on the use of the Huisgen cycloaddition between terminal alkynes and azides. KTGS is a captivating area of research offering an unprecedented and powerful strategy to probe the macromolecular complexity and dynamics of biological targets. After a brief introduction listing all chemical ligation reactions reported to date in KTGS, this review focuses on the last five years' progress to expand the repertoire of the click or "click-like" tool box targeting proteins, as well as to overcome limitations arising in particular from false negatives, i.e. potent ligands that are not formed, or formed in undetectable trace amounts. Furthermore, we wish to analyze the new twists and novelties described in some of these applications in order to better understand the conditions that govern this strategy and the extent to which it can be developed and generalized for a more efficient process.
authors.affiliation: Biomedical Sciences Research Council, University of St. Andrews, St. Andrews KY16 9ST, UK.
authors.forename: Emilia
authors.initials: E
authors.lastname: Oueis
authors.forename: Cyrille
authors.initials: C
authors.lastname: Sabot
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Renard
mesh_terms: D057930:Click Chemistry; D006801:Humans; D007700:Kinetics; D008024:Ligands; D046911:Macromolecular Substances / Q000138:chemical synthesis* / Q000737:chemistry; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D008024:Ligands; D046911:Macromolecular Substances; D011506:Proteins