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

preprint
submitted on 08.05.2020 and posted on 11.05.2020 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.

Funding

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

History

Email Address of Submitting Author

ssando@chembio.t.u-tokyo.ac.jp

Institution

The University of Tokyo

Country

Japan

ORCID For Submitting Author

0000-0003-0275-7237

Declaration of Conflict of Interest

The authors declare no competing financial interests.

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