The CREB binding protein (CBP) is a human transcriptional coactivator consisting 
of several conserved functional modules, which interacts with distinct 
transcription factors including nuclear receptors, CREB, and STAT proteins. 
Despite the importance of CBP in transcriptional regulation, many questions 
regarding the role of its particular domains in CBP functions remain unanswered. 
Therefore, developing small molecules capable of selectively modulating a single 
domain of CBP is of invaluable aid at unraveling its prominent activities. Here 
we report the design, synthesis, and biological evaluation of conformationally 
restricted peptides as novel modulators for the acetyl-lysine binding 
bromodomain (BRD) of CBP. Utilizing a target structure-guided and computer-aided 
rational design approach, we developed a series of cyclic peptides with affinity 
for CBP BRD significantly greater than those of its biological ligands, 
including lysine-acetylated histones and tumor suppressor p53. The best 
cyclopeptide of the series exhibited a K(d) of 8.0 μM, representing a 24-fold 
improvement in affinity over that of the linear lysine 382-acetylated p53 
peptide. This lead peptide is highly selective for CBP BRD over BRDs from other 
transcriptional proteins. Cell-based functional assays carried out in colorectal 
carcinoma HCT116 cells further demonstrated the efficacy of this compound to 
modulate p53 stability and function in response to DNA damage. Our results 
strongly argue that these CBP modulators can effectively inhibit p53 
transcriptional activity by blocking p53K382ac binding to CBP BRD and promoting 
p53 instability by changes of its post-translational modification states, a 
different mechanism than that of the p53 inhibitors reported to date.