Abstract
Recently, a variety of studies concerned with the permeability and oral bioavailability of cyclic peptides have been reported. In particular, strategies aiming at modifying peptides to maintain or to enhance solubility while enabling permeability constitute a significant challenge, but are of high interest to ensure a smooth drug discovery process. Current methodologies include N-methylation, matching of hydrogen bonding acceptors and donors across the macrocycle, and additional masking of polarity. In this study, we investigate further the pivotal effects of shielding on permeability and studied the metabolism of the corresponding peptides in more detail by comparing peptide concentrations in the portal versus the jugular vein in rats. Interestingly, minor changes in one particular side chain impacts both permeability and liver metabolism.Graphical
Highlights
The improvement of absorption, distribution, metabolism, and excretion (ADME) properties for peptides is of utmost importance to broaden applications for macromolecules, e.g. to enable delivery by the oral route
We introduced the concept of a polar surface assessment in 3D called solvent-accessible polar surface area (SAPSA), and showed the correlation of in vitro permeability on cyclic hexapeptides (1) and (2) (Fig. 1) with the in vivo oral bioavailability (%BAV) as indicated in Table 2 for peptides (1) and (2) (Lewis et al 2015)
We have shown how hydrophobic shielding can contribute to masking polarity, and thereby enhancing permeability, while simultaneously providing excellent solubility
Summary
The improvement of absorption, distribution, metabolism, and excretion (ADME) properties for peptides is of utmost importance to broaden applications for macromolecules, e.g. to enable delivery by the oral route. Principal studies to elucidate the role of the backbone and side chains for a given cyclic peptide with respect to permeability, and in particular oral uptake, are of value to learn more about the required property space. The promotion of permeability while maintaining a good solubility remains a significant challenge and is of interest in our investigation (Marzinzik and Vorherr 2013; Vorherr 2015; Kwon and Kodadek 2007) This intense effort on macromolecules has become extremely important, since for many attractive drug targets no high affinity and selective small molecules complying with the “rule-of-five” (Krämer et al 2016; Whitty et al 2016) can be identified. There is a need to obtain appropriate properties to render particular ligands druggable even though the route of administration requires transport across certain barriers, e.g. crossing the intestinal mucosa to achieve systemic exposure
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