RESUMO
Sp2-sp3 fragments play a vital role in fragment-based drug design (FBDD). Strategies to chemically modify them and efficiently access libraries of these compounds have been goals of the highest priority in the last decades. In this work, a series of sp2-sp3 fragments was synthesized and validated for that purpose, based on their measured physical-chemical properties. Selective C-H cyanation and allylation of these fragments was demonstrated by simple heating in presence of an appropriate hydrogen-atom transfer reagent and a radical acceptor. These conditions enabled a streamlined access to covalent fragments in a single step, by direct introduction of the desired covalent binder. Preliminary results on vinylation, as well as late-stage functionalization of a drug analogue were disclosed.
RESUMO
The nuclear coactivator binding domain (NCBD) of transcriptional co-regulator CREB-binding protein (CBP) is an example of conformationally malleable proteins that can bind to structurally unrelated protein targets and adopt distinct folds in the respective protein complexes. Here, we show that the folding landscape of NCBD contains an alternative pathway that results in protein aggregation and self-assembly into amyloid fibers. The initial steps of such protein misfolding are driven by intermolecular interactions of its N-terminal α-helix bringing multiple NCBD molecules into contact. These oligomers then undergo slow but progressive interconversion into ß-sheet-containing aggregates. To reveal the concealed aggregation potential of NCBD we used a chemically synthesized mirror-image d-NCBD form. The addition of d-NCBD promoted self-assembly into amyloid precipitates presumably due to formation of thermodynamically more stable racemic ß-sheet structures. The unexpected aggregation of NCBD needs to be taken into consideration given the multitude of protein-protein interactions and resulting biological functions mediated by CBP.