Stereochemistry Balances Cell Permeability and Solubility in the Naturally Derived Phepropeptin Cyclic Peptides

Abstract

Cyclic peptide (CP) natural products provide useful model systems for mapping "beyond-Rule-of-5" (bRo5) space. We identified the phepropeptins as natural product CPs with potential cell permeability. Synthesis of the phepropeptins and epimeric analogues revealed much more rapid cellular permeability for the natural stereochemical pattern. Despite being more cell permeable, the natural compounds exhibited similar aqueous solubility as the corresponding epimers, a phenomenon explained by solvent-dependent conformational flexibility among the natural compounds. When analyzing the polarity of the solution structures we found that neither the number of hydrogen bonds nor the total polar surface area accurately represents the solvation energies of the high and low dielectric conformations. This work adds to a growing number of natural CPs whose solvent-dependent conformational behavior allows for a balance between aqueous solubility and cell permeability, highlighting structural flexibility as an important consideration in the design of molecules in bRo5 chemical space.

Synthetic Cyclic Peptomers as Type III Secretion System Inhibitors

“…and previously characterized for their activity as weak proteasome inhibitors (29). It was shown previously that stereo-inversion of the Pro residue to form epiphepropeptin (EpD) significantly altered the compound conformation as determined by nuclear magnetic resonance (NMR) analysis (28). Thus, it is unlikely that the compounds described here as possessing T3SS-inhibitory activity would retain the proteasomal inhibition of the natural product.…”

“…As part of a previous study (28), a library of 20 synthetic peptides and peptomers based on the structure of a natural product, phepropeptin D (29), were synthesized and placed in an internal screening library. These peptomers were not previously screened for any bioactivity and may have a high intrinsic potential to disrupt protein-protein interactions (30), such as those critical for assembly of a large proteinaceous structure such as the T3SS.…”

Modulation of Oral Bioavailability and Metabolism for Closely Related Cyclic Hexapeptides

“…In addition, NMR (Wang et al 2014 ) has been shown to be a valuable tool to verify intramolecular hydrogen bonds, which are of prime importance in shielding polarity and in evaluating the effect of N -methylation on conformation. Design, and production of libraries inspired by peptidic natural products such as Sanguinamide A (Nielsen et al 2012 ), Guangomide A and Phepropeptide (Nielsen et al 2014 ; Hewitt et al 2015 ; Schwochert et al 2016 ) have also been demonstrated to be a promising strategy for the identification of permeable peptides and understanding the underlying principles. In particular, recent investigations on cyclic peptides derived from Sanguinamide A resulted in a molecule exhibiting solvent-dependent flexibility and improved permeability (Bockus et al 2015 ).…”

Solubility prediction in the bRo5 chemical space: where are we right now?

“…by possessing one important property favourable for development of drugs in bRo5 space. The solubility distribution of the subset suggested that a classification rather than a regression strategy should be applied (Figure 2), and the threshold to distinguish soluble (47) from poorly soluble (18) compounds was fixed at 50 M. This is a slightly more liberal cut-off than that proposed by GSK (30 M) to distinguish compounds having poor from those having intermediate solubility [2].…”