Stereochemical effects of all-hydrocarbon tethers in i,i+4 stapled peptides

doi:10.1016/j.bmcl.2009.03.022

Bioorganic & Medicinal Chemistry Letters

Volume 19, Issue 9, 1 May 2009, Pages 2533-2536

https://doi.org/10.1016/j.bmcl.2009.03.022 Get rights and content

Abstract

The stereochemical effects of the hydrocarbon crosslink on the conformation and cellular uptake of i,i+4 stapled peptides were studied. Compared to its S,S-configurated counterpart, the crosslink bearing the R,R-configuration provided a significantly diminished helix stabilizing effect and conferred less efficient cellular uptake on the stapled peptides. These results suggest that the vesicular trafficking pathway employed by cells to take up stapled peptides is sensitive to the extent of helical character in the peptide, with greater helicity conferring increased cellular uptake.

Graphical abstract

An analysis of stereochemical effects of the hydrocarbon crosslink on the helical stability and cellular uptake of i,i+4 stapled peptides reveals that S,S is superior in both respects to R,R.

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Acknowledgement

This research was supported by the Harvard and Dana-Farber Program in Cancer Chemical Biology.

References and notes (11)

C.E. Schafmeister et al.
J. Am. Chem. Soc.
(2000)
L.D. Walensky et al.
Science
(2004)
F. Bernal et al.
J. Am. Chem. Soc.
(2007)
L.D. Walentsky et al.
Mol. Cell
(2006)
Y.-H. Chen et al.
Biochemistry
(1972)
R. Fairman et al.
J. Am. Chem. Soc.
(1992)
E. Krause et al.
J. Am. Chem. Soc.
(2000)
J. Gamer et al.
Org. Biomol. Chem.
(2007)
L.K. Henchey et al.
Curr. Opin. Chem. Biol.
(2008)
G.L. Verdine et al.
Clin. Cancer Res.
(2007)

There are more references available in the full text version of this article.

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Stereochemical effects of all-hydrocarbon tethers in i,i+4 stapled peptides

Abstract

Graphical abstract

Section snippets

Acknowledgement

J. Am. Chem. Soc.

Science

J. Am. Chem. Soc.

Mol. Cell

Biochemistry

J. Am. Chem. Soc.

J. Am. Chem. Soc.

Org. Biomol. Chem.

Curr. Opin. Chem. Biol.

Clin. Cancer Res.