Synthesis of cell-permeable stapled BH3 peptide-based Mc1-1 inhibitors containing simple aryl and vinylaryl cross-linkers

TETRAHEDRON

卷:70

Article

Muppidi, Avinash¹  Doi, Kenichiro²  Ramil, Carlo P.¹  Wang, Hong-Gang²  Lin, Qing¹ 

[1] SUNY Buffalo, Dept Chem, Buffalo, NY 14260 USA

[2] Penn State Univ, Coll Med, Dept Pediat, Hershey, PA 17033 USA

关键词: Peptides;    Cross-linkers;    Stapled peptides;    Inhibitors;    Protein-protein interaction;   

DOI  :  10.1016/j.tet.2014.05.104

来源: Elsevier

【 摘 要 】

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. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

Free