mRNA-display macrocycles reveal CHD4 as an interaction hub in the NuRD complex
- mRNA display against CHD4's SANT-SLIDE domain yielded small macrocyclic peptides that block its interaction with GATAD2A, a core step in building the NuRD complex.
- The screen pointed to a second binding site on CHD4; CDK2AP1 was confirmed to bind there, and the CHD4–GATAD2A–CDK2AP1 ternary complex structure was determined.
- Disrupting NuRD induces fetal hemoglobin, a validated therapeutic strategy for sickle cell disease and other β-hemoglobinopathies.
💡 Points
One selection campaign delivering both hits and biology is a nice outcome. Macrocycles sitting on a protein–protein interface are rarely drug-like as they stand, so my question is whether the ternary structure lets us shrink them toward something cell-permeable; the second site on CHD4 gives another handle for that. I'd also want to see selectivity against related remodelers.