Overproduction or deregulation of the human protein c-Myc causes Burkitt's lymphoma and may be involved in breast, prostate and skin cancers. Inhibitors of c-Myc activity can cause induced tumor cell death, but none of the known c-Myc inhibitors are promising drug candidates. Due to their protease resistance and favorable pharmacodynamics, peptides of beta-amino acids are poised to overcome limitations of current c-Myc inhibitors. We propose to design beta peptides that target c-Myc, synthesize, and test these molecules for their ability to inhibit c-Myc and prevent the oncogenic transformation. One peptide design strategy will incorporate sequences known to drive helical formation and to present the epitope of the c-Myc binding partner Max in a structurally compatible fashion. A second strategy will involve selection of c-Myc binding peptides from a library of beta-peptides. Both strategies will be guided and analyzed by structural analysis of the c-Myc dimerization region. This research will extend existing methodologies for synthesis and evaluation of alpha-amino acid peptide libraries to beta-amino acids, advance beta-peptides as a general class of therapeutics and potentially generate novel agents for c-Myc related cancers. ? ?
| Daniels, Douglas S; Schepartz, Alanna (2007) Intrinsically cell-permeable miniature proteins based on a minimal cationic PPII motif. J Am Chem Soc 129:14578-9 |
