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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.

SUBMITTER: Muppidi A 

PROVIDER: S-EPMC3472523 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Muppidi Avinash A   Doi Kenichiro K   Edwardraja Selvakumar S   Drake Eric J EJ   Gulick Andrew M AM   Wang Hong-Gang HG   Lin Qing Q  

Journal of the American Chemical Society 20120904 36


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  ...[more]

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