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Short Helix-Constrained Peptides With Contiguous Hydrophobic and Charged Surface Patches Are Cell Permeable

Abstract

Most protein-protein interactions occur inside cells. Peptides inhibit protein-protein interactions but tend not to enter cells. We compare cell permeability for 8-12 residue peptides with helix-inducing lactam/hydrocarbon linkers between amino acid sidechains. Cell uptake increases when hydrophobic residues and lactam linkers (i, i+4) form a contiguous hydrophobic surface patch. Uptake further increases when both hydrophobic and positively charged (not neutral or negative) residues are clustered into amphipathic surfaces. Changing the linker from a lactam to a hydrocarbon further increases uptake, but also promotes cell lysis. Helicity, positively charged residues and amphipathicity contributed to optimal cell permeability. Most known bioactive helical peptides do not optimally cluster residues for amphipathicity and may be unoptimised for cell uptake

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Publication details

The article was accepted on 06 Dec 2017 and first published on 06 Dec 2017


Article type: Communication
DOI: 10.1039/C7OB02952G
Citation: Org. Biomol. Chem., 2017, Accepted Manuscript
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    Short Helix-Constrained Peptides With Contiguous Hydrophobic and Charged Surface Patches Are Cell Permeable

    S. R. Perry, T. A. Hill, A. D. de Araujo, H. N. Hoang and D. P. Fairlie, Org. Biomol. Chem., 2017, Accepted Manuscript , DOI: 10.1039/C7OB02952G

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