Overall, I hope that 2026 will yield at least the same degree of scientific progress as 2025. (12/12)

#Chemistry #ChemBio #Science #Antibiotics #Synthesis #TPD #Degrader #Proteomics #Kinases #RNA #Screening #CovalentInhibitors #DirectToBiology

Direct Cellular Screening of Pd-Mediated Arylation of Cyclic Peptide Binders Targeting Ubiquitin Chains: Toward Modulating NEMO Liquid–Liquid Phase Separation Ubiquitination is a critical post-translational modification that regulates key cellular processes such as protein degradation and DNA damage repair. Targeting a specific type of ubiquitin chain (e.g., Lys48 or Lys63-linked ubiquitin chain) via cyclic peptides presents a new strategy to modulate biological processes with therapeutic potential for various diseases. However, such a strategy remains challenging due to the obstacles of cell permeability and bioactivity. Here, we present a new method that directly assesses these parameters by integrating palladium-mediated Cys arylation with direct cellular screening. Using CP4, a previously identified cyclic peptide modulator of Lys63-linked ubiquitin chains, we generated a focused library of arylated analogues and optimized the Pd-mediated arylation for direct cellular screening. We discovered a new analog, CP-P12-ArH, that demonstrated enhanced binding affinity and robust bioactivity, as evidenced by increased γ-H2AX phosphorylation and apoptosis induction in cancer cells. Furthermore, CP-P12-ArH effectively inhibited the in vitro formation of NF-κB essential modulator (NEMO) biomolecular condensates by disrupting the elongation of Lys63-linked ubiquitin chains, offering a novel way to modulate NF-κB signaling. This work establishes a generalizable platform for the rapid optimization of cyclic peptide therapeutics targeting protein–protein interactions.

Interesting paper by the group of Ashraf Brik in @jacs.acspublications.org. Pd-mediated modification of cyclic peptides allows to combinatorially generate S-arylated derivatives and directly screen them for activity in cells.

pubs.acs.org/doi/10....
#ChemSky #ChemBio #DirectToBiology #D2B