How Structural Features Influence the Biomembrane Permeability of Peptides

Abstract

Successful drug development requires not only optimization of specific and potent pharmacological activity at the target site, but also efficient delivery to that site. Many promising new peptides with novel therapeutic potential for the treatment of AIDS, cardiovascular diseases, and CNS disorders have been identified, yet their clinical utility has been limited by delivery problems. Along with metabolism, a major factor contributing to the poor bioavailability of peptides is thought to be inefficient transport across cell membranes. At the present time, the reasons for this poor transport are poorly understood. To explore this problem, we have designed experiments focused on determining the relationship between peptide structure and peptide transport across various biological membranes both in vitro and in vivo. Briefly, peptides that varied systematically in chain length, lipophilicity, and amide bond number were prepared. Permeability results with these solutes support a model in which the principal determinant of peptide transport is the energy required to desolvate the polar amides in the peptide for the peptide to enter and diffuse across the cell membrane. Further impacting on peptide permeability is the presence of active, secretory transport systems present in the apical membrane of intestinal epithelial and brain endothelial cells. In Caco-2 cell monolayers, a model of the human intestinal mucosa, this pathway displayed substrate specificity, saturation, and inhibition. Similar results have been shown in vivo in both rat intestinal and blood-brain barrier absorption models. The presence of such systems serves as an additional transport barrier by returning a fraction of absorbed peptide back to the lumen.

Novel Delivery Systems for Improving the Clinical Use of Peptides

“…Three routes are available for peptide absorption through epithelia, similar to other drugs or xenobiotics, namely, 1) through the cells (transcellular), 2) through intercellular junctions (paracellular), or 3) by active transport or receptor-mediated mechanisms (Burton et al, 1996;Boguslavsky et al, 2003). It is typically proposed that most peptides are absorbed via the paracellular route (Patton, 1996;Veuillez et al, 2001;Lin, 2009;Ozsoy et al, 2009).…”

“…The most important factors limiting the permeability of peptides through the epithelia are an increased number of hydrogen bonds, hydrophilicity, and molecular size greater than 700 Da (Burton et al, 1996;Ramaswami et al, 1996;Lin, 2009;Ozsoy et al, 2009;Diao and Meibohm, 2013). The transcellular transport across the lipophilic cell membranes is limited by the peptide's polarity, and paracellular permeation is restricted by their large size (He et al, 1998;Lin, 2009).…”

Spatial expression patterns of peptide transporters in the human and rat gastrointestinal tracts, Caco-2 In Vitro cell culture model, and multiple human tissues

“…Peptides and peptide-based agents, due largely to multiple side chain functionalities, tend to be polar molecules that do not readily traverse biological barriers via passive diffusion (1,(7)(8)(9)(10)(11). In the past several years, considerable work has been performed to explore the active peptide transporters that are known to facilitate peptide transport (5,12,13).…”

Transcellular Transport of a Highly Polar 3+ Net Charge Opioid Tetrapeptide

“…Although enzymatic degradation can be overcome by a variety of structural modifications, the ability of peptides to distribute to their site(s) of action remains a significant problem. Besides insufficient lipophilicity, this low permeability is also due to the high capacity of the peptide backbone to bind water molecules through hydrogen bonding (Burton et al, 1996). Attempts at modifying polar oligopeptides with lipid groups have only been met with limited success, and such modifications often resulted in a decline of biological activity.…”