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Org Lett. 2015 Jun 19;17(12):2928-31. doi: 10.1021/acs.orglett.5b01162. Epub 2015 Jun 5.

Peptide to Peptoid Substitutions Increase Cell Permeability in Cyclic Hexapeptides.

Author information

1
†Chemistry and Biochemistry University of California, Santa Cruz, California 95064, United States.
2
‡Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States.
3
∥World Wide Medicinal Chemistry, Groton Laboratories, Pfizer Inc. Groton, Connecticut 06340, United States.
4
§Pharmacokinetics and Drug Metabolism, Cambridge Laboratories, Pfizer Inc. Cambridge, Massachusetts 02139, United States.
5
⊥Pharmacokinetics and Drug Metabolism, Groton Laboratories, Pfizer Inc. Groton, Connecticut 06340, United States.
6
○World Wide Medicinal Chemistry, Cambridge Laboratories, Pfizer Inc. Cambridge, Massachusetts 02139, United States.

Abstract

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.

PMID:
26046483
DOI:
10.1021/acs.orglett.5b01162
[Indexed for MEDLINE]

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