Synthesis of cell-permeable stapled BH3 peptide-based Mcl-1 inhibitors containing simple aryl and vinylaryl cross-linkers

Avinash Muppidi, Kenichiro Doi, Carlo P. Ramil, Hong-Gang Wang, Qing Lin

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

We report the synthesis of a series of distance-matching aryl and vinylaryl cross-linkers for constructing stapled peptides containing cysteines at i,i+7 positions. Langevin dynamics simulation studies helped to classify these cross-linkers into two categories: the rigid cross-linkers with narrower S-S distance distribution and the flexible cross-linkers with wider S-S distance distribution. The stapled Noxa BH3 peptides with the flexible distance-matching cross-linkers gave the highest degree of helicity as well as the most potent inhibitory activity against Mcl-1. However, the stapled peptides with the highest hydrophobicity showed the most efficient cellular uptake. Together, this work illustrates the divergent nature of binding affinity and cellular uptake, and the vital importance of choosing appropriate cross-linkers in constructing stapled peptides with the drug-like properties.

Original languageEnglish (US)
Pages (from-to)7740-7745
Number of pages6
JournalTetrahedron
Volume70
Issue number42
DOIs
StatePublished - Oct 21 2014

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Peptides
Noxae
Hydrophobicity
Hydrophobic and Hydrophilic Interactions
Cysteine
Computer simulation
Pharmaceutical Preparations
Bax protein (53-86)

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Muppidi, Avinash ; Doi, Kenichiro ; Ramil, Carlo P. ; Wang, Hong-Gang ; Lin, Qing. / Synthesis of cell-permeable stapled BH3 peptide-based Mcl-1 inhibitors containing simple aryl and vinylaryl cross-linkers. In: Tetrahedron. 2014 ; Vol. 70, No. 42. pp. 7740-7745.
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Synthesis of cell-permeable stapled BH3 peptide-based Mcl-1 inhibitors containing simple aryl and vinylaryl cross-linkers. / Muppidi, Avinash; Doi, Kenichiro; Ramil, Carlo P.; Wang, Hong-Gang; Lin, Qing.

In: Tetrahedron, Vol. 70, No. 42, 21.10.2014, p. 7740-7745.

Research output: Contribution to journalArticle

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