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 journalArticle

100 Citations (Scopus)

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 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
Volume134
Issue number36
DOIs
StatePublished - Sep 12 2012

Fingerprint

Peptides
Permeability
Noxae
Proteins
U937 Cells
Methylation
Chemical modification
Protein Transport
Cysteine
Substitution reactions
Crystal structure

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Muppidi, Avinash ; Doi, Kenichiro ; Edwardraja, Selvakumar ; Drake, Eric J. ; Gulick, Andrew M. ; Wang, Hong-Gang ; Lin, Qing. / Rational design of proteolytically stable, cell-permeable peptide-based selective Mcl-1 inhibitors. In: Journal of the American Chemical Society. 2012 ; Vol. 134, No. 36. pp. 14734-14737.
@article{e3a3940121f54d3b99e4606d71b5467b,
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 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.",
author = "Avinash Muppidi and Kenichiro Doi and Selvakumar Edwardraja and Drake, {Eric J.} and Gulick, {Andrew M.} and Hong-Gang Wang and Qing Lin",
year = "2012",
month = "9",
day = "12",
doi = "10.1021/ja306864v",
language = "English (US)",
volume = "134",
pages = "14734--14737",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "36",

}

Rational design of proteolytically stable, cell-permeable peptide-based selective Mcl-1 inhibitors. / Muppidi, Avinash; Doi, Kenichiro; Edwardraja, Selvakumar; Drake, Eric J.; Gulick, Andrew M.; Wang, Hong-Gang; Lin, Qing.

In: Journal of the American Chemical Society, Vol. 134, No. 36, 12.09.2012, p. 14734-14737.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rational design of proteolytically stable, cell-permeable peptide-based selective Mcl-1 inhibitors

AU - Muppidi, Avinash

AU - Doi, Kenichiro

AU - Edwardraja, Selvakumar

AU - Drake, Eric J.

AU - Gulick, Andrew M.

AU - Wang, Hong-Gang

AU - Lin, Qing

PY - 2012/9/12

Y1 - 2012/9/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84866419568&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866419568&partnerID=8YFLogxK

U2 - 10.1021/ja306864v

DO - 10.1021/ja306864v

M3 - Article

VL - 134

SP - 14734

EP - 14737

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 36

ER -