Treatment of Clostridioides difficile infections (CDI) with vancomycin is associated with high relapse rates. In this study, the experimental glycopeptide antibiotic EVG7 was found to effectively trea...

The introduction of a single C-atom into organic substrates typically results in the formation of flat molecules containing unsaturated C(sp)-centers. Adding a single C(sp3)-atom surrounded by four σ-...

We report a ‘direct-to-biology’ (D2B) approach for optimising covalent acrylamide binders of protein targets and apply this to the identification of a selective and cell-active inhibitor of Werner (WR...

SNAr reactions were remarkably accelerated using a pretargeting and activating unit based on dynamic covalent chemistry (DCvC). A Cys attack at the C–F bond on the aromatic ring of salicylaldehyde derivatives was only observed upon iminium formation with a neighboring Lys residue of model small peptides. Such self-activation was ascribed to the stronger electron-withdrawing capability of the iminium bond with respect to that of the parent aldehyde that stabilized the transition state of the reaction, together with the higher preorganization of the reactive groups in the cationic aldiminium species. This approach was further applied for the functionalization of two antibodies. In both cases, the presence of the aldehyde group in close proximity to the reactive C–F bond resulted in a noteworthy increase in bioconjugation yields, with excellent chemo-selectivity. Whereas the modification of an IgG1 antibody led to stochastic product distributions, microenvironment selectivity was noted when employing IgG4, in line with the lower number of Lys residues in the hinge region of the latter. Additionally, the postfunctionalization of the modified antibodies was attained through the dynamic covalent exchange of the tethered iminium derivative with hydrazides, representing an unprecedented “tag and modify” selective bioconjugation strategy based on DCvC.

Abstract. The NRF2 transcription factor is constitutively active in cancer where it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2-depen...

Affinity-selection platforms are powerful tools in early drug discovery, but current technologies such as DNA-encoded libraries (DELs) are limited by synthesis complexity and incompatibility with nucl...

The enzyme PCMT1 was found to install a C-terminal cyclic imide modification on proteins that marks them for degradation by CRBN, uncovering a conserved protein turnover pathway with implications in m...

Small-molecule ligands have been developed that covalently attach to their cognate RNA aptamers in vitro and in living cells. This strategy opens up new avenues for RNA imaging applications (for examp...

The human genome encodes 518 protein kinases that are pivotal for drug discovery in various therapeutic areas, such as cancer and autoimmune disorders…