title: Rational design of proteolytically stable, cell-permeable peptide-based selective Mcl-1 inhibitors.
abstract: 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.
authors.affiliation: Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 14260-3000, USA.
authors.forename: Avinash
authors.initials: A
authors.lastname: Muppidi
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Doi
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Edwardraja
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Drake
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Gulick
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Lin
mesh_terms: D002463:Cell Membrane Permeability / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D020298:U937 Cells
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2