Rational Design of Proteolytically Stable, Cell-Permeable Peptide‑Based Selective Mcl‑1 Inhibitors

• Published in: Journal of the American Chemical Society Vol. 134; no. 36; pp. 14734 - 14737
• Main Authors: Muppidi, Avinash, Doi, Kenichiro, Edwardraja, Selvakumar, Drake, Eric J, Gulick, Andrew M, Wang, Hong-Gang, Lin, Qing
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12.09.2012
• Subjects: Cell Membrane Permeability - drug effects; Humans; Models, Molecular; Molecular Structure; Myeloid Cell Leukemia Sequence 1 Protein; Peptides - chemistry; Peptides - pharmacology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - metabolism; U937 Cells
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja306864v

Direct chemical modifications provide a simple and effective means to “translate” bioactive helical peptides into potential therapeutics targeting intracellular protein–protein interactions. We previously showed that distance-matching bisaryl cross-linkers can reinforce peptide helices containing two cysteines at the i and i+7 positions and confer cell permeability to the cross-linked peptides. Here we report the first crystal structure of a biphenyl-cross-linked Noxa peptide in complex with its target Mcl-1 at 2.0 Å resolution. Guided by this structure, we remodeled the surface of this cross-linked peptide through side-chain substitution and N-methylation and obtained a pair of cross-linked peptides with substantially increased helicity, cell permeability, proteolytic stability, and cell-killing activity in Mcl-1-overexpressing U937 cells.