Poster Presentation 14th Australian Peptide Conference 2022

Engineering pasireotide analogs for oral peptide delivery (#201)

Celine Hung 1 , Philip Thompson 1 , David Chalmers 1 , Colin Pouton 1
  1. Monash University, Parkville, VICTORIA, Australia

Oral bioavailability of peptides has long been a significant barrier to a wider application of peptide therapeutics and is generally accepted to be due to its poor permeability and high enzymatic degradation.  Perhaps the most common exception to this observation is Cyclosporin A whose cyclic nature and hydrophobic moieties have uniquely allowed good oral absorption and subsequent bioavailability.  Further research into this phenomenon found that it is not enough to simply synthesise a peptide with only hydrophobic residues, but the compound's overall conformation in varying environments greatly dictates the compound's likelihood to be permeable across a membrane.  Our research has found that singular changes to stereochemistry in pasireotide analogs can improve peptide permeability by 3-fold in PAMPA assays.  This highlights the importance of conformation to unlocking peptide permeability and will be explored further using computational modelling.  For oral absorption of a peptide to be possible there must be a delicate balance between reduction of hydrogen bonding potential in the compound without losing bioactivity of the drug, and achieving a specific or several key conformations to allow for permeation.  Then, there must be sufficient enzymatic stability once in the bloodstream.  This study will explore this balance by synthesising a series of pasireotide analogs with the modification aim of improving permeability whilst maintaining functional bioactivity using a series of in vitro assays.