Mechanistic Studies of Membrane Permeation of Peptides

Oral administration of drugs is often preferred over injections due to its convenience, and therapeutic peptides offer significant advantages, including high activity, specificity, and low toxicity. However, oral delivery of peptide drugs presents significant challenges such as low permeability across the gastrointestinal epithelium. A promising strategy to improve bioavailability is co-formulating peptides with permeation enhancers (PEs) to facilitate transcellular transport. In this thesis, the interactions between peptides, PEs, and lipid membranes have been investigated using both the atomistic all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) simulations. We investigated the interactions between PE and membrane using AA-MD. The PEs studied were different medium-chain fatty acids, such as laurate, caprate (C10), and caprylate, and the caprylate derivative SNAC all with a negative charge and neutral caprate and neutral sucrose monolaurate. Our results indicated that the PEs, once incorporated into the membrane, induce membrane leakiness in a concentration-dependent manner. The results also indicated that a PE concentration of at least 70−100 mM is needed to strongly affect transcellular permeability. We then studied the colloidal structures of different peptide therapeutics in the presence and absence of two different PEs, C10 and SNAC and bile salt, taurocholate. The simulations provided insights into molecular-level interactions, highlighting the specific contacts between peptide residues responsible for aggregation and the interactions between peptide residues and permeability enhancers/taurocholates that are crucial within the mixed colloids. Our simulations also showed that the PEs can promote the release of hydrophobic peptides while restrict the release of water-soluble peptides. Finally, we also performed umbrella sampling simulations to calculate the effective permeability coefficients (Peff) for three different peptides: octreotide, desmopressin, and triptorelin, using CG-MD in the presence of C10 and SNAC in the membrane. The results show that C10 can increase the Peff, of the peptides included in orders of magnitude in a concentration-dependent manner, compared to the peptide systems without C10 present. These molecular-level insights can guide the design of improved permeability enhancer-based dosage forms, allowing for selecting the best possible peptide-PE combination and precise control of peptide release profiles near the intended absorption site.