Peptide to Peptoid Substitutions Increase Cell Permeability in Cyclic Hexapeptides

by Joshua Schwochert, Rushia Turner, Melissa Thang, Ray F Berkeley, Alexandra R Ponkey, Kelsie M. Rodriguez, Siegfried S F Leung, Bhagyashree Khunte, Gilles Goetz, Chris Limberakis, Amit S. Kalgutkar, Heather Eng, Michael J. Shapiro, Alan M. Mathiowetz, David A. Price, Spiros Liras, Matthew P. Jacobson, and R. Scott Lokey

The effect of peptide-to-peptoid substitutions on the passive membrane permeability of an N-methylated cyclic hexapeptide is examined. In general, substitutions maintained permeability but increased conformational heterogeneity. Diversification with nonproteinogenic side chains increased permeability up to 3-fold. Additionally, the conformational impact of peptoid substitutions within a β-turn are explored. Based on these results, the strategic incorporation of peptoid residues into cyclic peptides can maintain or improve cell permeability, while increasing access to diverse side-chain functionality…

June 5, 2015
ACS Publications – Organic Letters
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