Development and applications of inverse-electron-demand Diels-Alder reaction in bioorthogonal chemistry

Inverse-electron-demand Diels-Alder (IEDDA) reaction has become the most attractive bioorthogonal reaction due to its advantages of good biocompatibility, high reaction specificity and fast reaction kinetics. Therefore, extensive studies have been conducted in terms of reaction mechanism, reactants synthesis, chemistry optimization, biological applications, etc ., for IEDDA ligation and cleavage reactions respectively. In this review, first of all, we introduce the development and optimizations of the IEDDA reaction, followed by its biological applications including biomolecules labeling, protein manipulation, activation, drug delivery, pharmacokinetics study, prodrug releasing, siRNA activation and solid phase RNA purification. At last, we envision that further studies and applications of the IEDDA reaction are in demand, and expect that by exploring more optimized reaction pairs and wider biological applications, the research area of bioorthogonal chemistry would rush into a new era.