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

Abstract

<div> <div> <div> <p>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 CDCl<sub>3</sub>, 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. </p> </div> </div> </div>

Bioisostere Effects on the EPSA of Common Permeability-Limiting Groups

“…29 In accordance with this observation, the lesser dipole embedded within 1,2,4-oxadiazoles led to reductions in EPSA on the order of Δavg = -12±9 when compared to matched amide counterparts. We found that N-methylation (Δavg = -12±5) 30 , 31 and ester substitution (Δavg = -15±9) 32,33 were among the simplest and most effective tactics to reduce the EPSA of amide-containing compounds, a finding presaged by the abundance of these groups in naturally occurring, permeable macrocyclic peptides. 34 Thus, among common amide bioisosteres that preserve the parent group's HBA capacity while removing its donor function, only 1,2,3-triazoles failed to reliably reduce EPSA.…”

Accelerating Drug Discovery: Synthesis of Complex Chemotypes via Multicomponent Reactions

“…21 The amide-to-ester substitution in cyclic peptides has been shown to increase membrane permeability. 22,23 In an effort to expand the scope of the Passerini reaction, Brunelli and co-workers produced a library of 43 α-acyloxy carboxamides to evaluate the effects of substitution on the metabolic stability of the resulting ester moiety (Scheme 2). 20 Particular focus was given to the carboxylic acids and aldehydes, selecting diverse substrate models from aliphatic to substituted aromatic compounds.…”