The discovery of new chemical reactions is a long-standing goal of organic chemists. For decades, synthetic problems motivated the development of new methodologies to continuously expand the reaction toolkit in organic synthesis. As alternatives to purely rational approaches, strategies that offer more room for serendipity have recently emerged. In these approaches, the discovery is a result of the systematic exploration of a large number of chemical reactions through the use of robust high-throughput screening methods based either on mass spectrometry techniques [1] or on DNA technologies. [2] Although this strategy was already proven to be efficient with the discovery of several new interesting reactions, [3] this does not guarantee the potential impact of the discovered reactions. A more powerful approach would be the increase of the level of selection in a manner that only powerful reliable reactions are discovered. Such a highly demanding selection should therefore be based not only on reaction efficiencies, but also on other parameters that would ensure the usefulness of the discovered reaction. In 2001, K. B. Sharpless introduced the concept of "click chemistry", which has been widely and successfully applied since then, and listed a series of important criteria that may influence the extent and the impact of a chemical reaction. [4] Among them, chemoselectivity, simplicity of reaction conditions, and high efficiency, even in complex media, are probably the most important ones. This can be highlighted by the startling number of applications in organic synthesis, materials science, and biotechnology of the copper-catalyzed alkyne-azide cycloaddition reaction (CuAAC), which is one of the most powerful click reactions described to date. [5] Herein, we disclose an approach to accelerate the discovery of such important chemical reactions through the use of an immunoassay technique. As we previously described, [6] sandwich immunoassays can be successfully applied to monitor cross-coupling reactions by connecting small-molecule tags to chemically reactive groups. Products of bond-forming coupling reactions can then be specifically detected by two specific antitag monoclonal antibodies (mAbs) using standard ELISA techniques: one mAb captures the doubletagged coupling product on a solid phase and a second acts as a detector. We recently showed that the throughput of this adapted immunoassay (typically around 1000 analyses per day and person) allows the fast identification of new reactions among thousands of combinations of reactive functions and catalysts. [7] One crucial advantage of this screening method relies on the high specificity of mAbs, permitting the precise and sensitive quantification of the double-tagged crosscoupling products in complex mixtures without work-up. Here, we decided to fully exploit this advantage by designing a series of successive screening in order to identify new, efficient, chemoselective, and biocompatible [3+2] cycloaddition reactions. Our approach (Figure 1) involves three mai...

A drug delivery system targeting the tumour microenvironment produces outstanding therapeutic efficacy on triple-negative mammary and pancreatic models.

Antibody−oligonucleotide conjugates (AOCs) are a novel class of synthetic chimeric biomolecules that has been continually gaining traction in different fields of modern biotechnology. This is mainly due to the unique combination of the properties of their two constituents, exceptional targeting abilities and antibody biodistribution profiles, in addition to an extensive scope of oligonucleotide functional and structural roles. Combining these two classes of biomolecules in one chimeric construct has therefore become an important milestone in the development of numerous biotechnological applications, including imaging (DNA-PAINT), detection (PLA, PEA), and therapeutics (targeted siRNA/antisense delivery). Numerous synthetic approaches have been developed to access AOCs ranging from stochastic chemical bioconjugation to site-specific conjugation with reactive handles, introduced into antibody sequences through protein engineering. This Review gives a general overview of the current status of AOC applications with a specific emphasis on the synthetic methods used for their preparation. The reported synthetic techniques are discussed in terms of their practical aspects and limitations. The importance of the development of novel methods for the facile generation of AOCs possessing a defined constitution is highlighted as a priority in AOC research to ensure the advance of their new applications.

We report the discovery of a new bioorthogonal click-and-release reaction involving iminosydnones and strained alkynes. This transformation leads to two products resulting from the ligation and fragmentation of iminosydnones under physiological conditions. Optimized iminosydnones were successfully used to design innovative cleavable linkers for protein modification, thus opening up new areas in the fields of drug release and target-fishing applications. This click-and-release technology offers the possibility of exchanging tags on proteins for functionalized cyclooctynes under mild and bioorthogonal conditions.