These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
2 files

Amide-to-Ester Substitution Improves Membrane Permeability of a Cyclic Peptide Without Altering Its Three-Dimensional Structure

submitted on 08.05.2020, 15:37 and posted on 11.05.2020, 07:44 by Yuki Hosono, Jumpei Morimoto, Chad Townsend, Colin N. Kelly, Matthew R. Naylor, Hsiau-Wei Lee, R. Scott Lokey, Shinsuke Sando

Cyclic peptides are attractive molecules as inhibitors with high affinity and selectivity against intracellular protein-protein interactions (PPIs). On the other hand, cyclic peptides generally have low passive cell-membrane permeability, which makes it difficult to discover cyclic peptides that efficiently permeate into cells and inhibit intracellular PPIs. Here, we show that backbone amide-to-ester substitutions are useful for improving membrane permeability of peptides. Permeability in a series of model dipeptides increased upon amide-to-ester substitution. Amide-to-ester substitutions increased permeability in the same manner as amide-to-N-methyl amide substitutions, which are conventionally used for increasing permeability. Furthermore, amide-to-ester substitutions of exposed amides of a cyclic peptide successfully improved permeability. Conformational studies of the cyclic peptides using NMR and molecular mechanics calculations revealed that an amide-to-ester substitution of an exposed amide bond did not affect its low-energy conformation in CDCl3, in contrast with an N-methyl amide substitution. We envision that amide-to-ester substitution will be a potentially useful strategy for rational design of bioactive peptides with high membrane permeability.


CREST (#JPMJCR13L4), Japan Science and Technology Agency

Grant-in-Aid for Young Scientists (#19K15692) from the Japan Society for the Promotion of Science

National Institute of General Medical Sciences (NIGMS) (#GM131135), United States Department of Health and Human Services


Email Address of Submitting Author


The University of Tokyo



ORCID For Submitting Author


Declaration of Conflict of Interest

The authors declare no competing financial interests.


Logo branding