Rational design of proteolytically stable, cell-permeable peptide-based selective Mcl-1 inhibitors

Avinash Muppidi, Kenichiro Doi, Selvakumar Edwardraja, Eric J. Drake, Andrew M. Gulick, Hong Gang Wang, Qing Lin

Research output: Contribution to journalArticlepeer-review

135 Scopus citations


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 a 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.

Original languageEnglish (US)
Pages (from-to)14734-14737
Number of pages4
JournalJournal of the American Chemical Society
Issue number36
StatePublished - Sep 12 2012

All Science Journal Classification (ASJC) codes

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


Dive into the research topics of 'Rational design of proteolytically stable, cell-permeable peptide-based selective Mcl-1 inhibitors'. Together they form a unique fingerprint.

Cite this