Molecular design of Stat3-derived peptide selectivity between BET proteins Brd2 and Brd4 in ovarian cancer.

Stat3 signaling has been recognized as a potential therapeutic target of human ovarian cancer. The signaling is transducted through the peptide-medicated interaction of Stat3 with BET family members Brd2 and Brd4 -- 2 highly homologous proteins involved in differential downstream pathways. Here, we reported a successful design of peptide selectivity between the Brd2 and Brd4. The design resulted in 3 linear peptides SMSLQCXYLGVA, QSKVLTXSYWGA, and RQCNLGXLYMNY with high or moderate selectivity for Brd2 over Brd4 (S = 3.3-fold, 6.8-fold, and 4.2-fold, respectively) as compared with the native Stat3 peptide 281 HNLLRIXQFLQS292 (S = 2.5-fold). Structural analysis revealed that peptide N-terminus and hydrogen bonds play important roles in the peptide interaction stability and specificity with Brd2 and Brd4. This study would help to establish an integrated in silico-in vitro method for rational molecular design of peptide ligand selectivity between homologous protein receptors.