Recognition of the CREB-Binding Protein/Mixed Lineage Leukemia Interface by Sulfonyl-γ-AApeptides: Beyond Mimicry of Mixed Lineage Leukemia

The
kinase-inducible (KIX) domain, a structured region
within the
transcriptional coactivators CREB-binding protein (CBP) and p300,
serves as a docking site for multiple transcription factors, including
the mixed lineage leukemia (MLL) protein. The MLL–KIX protein–protein
interaction (PPI) has been implicated in various diseases, such as
leukemia, cancer, and neurodegenerative disorders, including Alzheimer’s
disease. In this study, we developed a series of MLL-mimicking peptidomimetic
foldamers based on a sulfonyl-γ-AApeptide backbone. These helical
foldamers successfully mimic the folded transactivation domain (TAD)
of MLL and bind the KIX domain with a high affinity. Consistent with
the notion that MLL–KIX interaction can allosterically enhance
CREB signaling, we found that the sulfonyl-γ-AApeptides strongly
stimulate CREB-dependent gene expression. Moreover, they exhibit no
significant cytotoxicity under the tested conditions, demonstrating
both binding specificity and therapeutic potential for targeting CREB-related
pathways in neurodegenerative disorders.