THE RELATIONSHIP BETWEEN PEPTIDE STRUCTURE AND TRANSPORT ACROSS EPITHELIAL-CELL MONOLAYERS

The successful development of orally bioavailable peptides and peptide -like substances as therapeutic agents will require an understanding o f how structure influences absorption across the intestinal mucosa. In an attempt to define such relationships, homologous series of peptide s were prepared which varied in lipophilicity, chain length and number of polar functionalities, and permeability studies conducted across C aco-2 cell monolayers as a model of the intestinal mucosa. The results suggested that the number of polar groups in the peptide, which presu mably require desolvation before transfer of the peptide into the cell membrane, was a principal determinant of transport. Consistent with t his hypothesis, two experimental methods of determining desolvation po tential were found to correlate well with the observed permeability re sults for the peptides. The insights gained from these studies were us ed in an attempt to rationally modify a renin inhibitory peptide, in o rder to improve its permeability across the intestinal mucosa. Based o n the results of this work, it is argued that a peptide must possess a delicate balance of affinity for the aqueous-membrane interface and a reasonably low desolvation energy in order for it to efficiently cros s an epithelial cell membrane.