Design of p53-derived peptides with cytotoxicity on breast cancer.
The tumor suppressor p53 plays essential role in conserving stability by preventing genome mutation, which is inactivated naturally by its negative regulator MDM2. Thus, targeting p53-MDM2 protein-protein interaction has been raised as a new cancer therapy in the medicinal community. In the current study, we report a successful application of an integrative protocol to design novel p53-derived peptides with cytotoxicity on human breast cancer cells. A quantitative structure-activity relationship-improved statistical potential was used to evaluate the binding potency of totally 24,054 single- and dual-point mutants of p53 peptide to MDM2 in a high-throughput manner, from which 46 peptide mutants with high predicted affinity and typical helical feature were involved in a rigorous modeling procedure that employed molecular dynamics simulations and post-binding energy analysis to systematically investigate the structural, energetic and dynamic aspects of peptide interactions with MDM2. Subsequently, a biological analysis was performed on a number of promising peptide candidates to determine their cytotoxic effects on human breast cancer cell line MDF-7. Six dual-point mutants were found to have moderate or high activities with their IC50 values ranging from 16.3 to 137.0 μM, which are better than that of wild-type p53 peptide (IC50 = 182.6 μM) and close to that of classical anticancer agent cis-platin (IC50 = 4.3 μM). Further, the most active peptide ETFSDWWKLLAE was selected as parent to further derive new mutants on the basis of the structural and energetic profile of its complex with MDM2. Consequently, three triple-point mutants (LTFSDWWKLLAE, ESFSDWWKLLAE and ETFADWWKLLAE) were obtained, and their biological activities (IC50 = 15.1, 27.0 and 8.7 μM, respectively) were determined to be comparable or better than the parent (IC50 = 16.3 μM).
Department of Breast Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Yi
Y
Fang
Rongzhong
R
Jin
Yinqi
Y
Gao
Jidong
J
Gao
Jing
J
Wang
D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D015195:Drug Design; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D017354:Point Mutation; D011485:Protein Binding / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000138:chemical synthesis* / Q000235:genetics / Q000494:pharmacology*
D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2