HOW STRUCTURAL FEATURES INFLUENCE THE BIOMEMBRANE PERMEABILITY OF PEPTIDES

Successful drug development requires not only optimization of specific and potent pharmacological activity at the target site, but also effi cient delivery to that site. Many promising new peptides with novel th erapeutic potential for the treatment of AIDS, cardiovascular diseases , and CNS disorders have been identified, yet their clinical utility h as been limited by delivery problems. Along with metabolism, a major f actor 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 explor e this problem, we have designed experiments focused on determining th e relationship between peptide structure and peptide transport across various biological membranes both in vitro and in vivo. Briefly, pepti des that varied systematically in chain length, lipophilicity, and ami de bond number were prepared. Permeability results with these solutes support a model in which the principal determinant of peptide transpor t 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, secretor y transport systems present in the apical membrane of intestinal epith elial and brain endothelial cells. In Caco-2 cell monolayers, a model of the human intestinal mucosa, this pathway displayed substrate speci ficity, 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 barri er by returning a fraction of absorbed peptide back to the lumen.