Oral delivery of peptides is highly desirable because it can greatly improve patient compliance, especially for early-stage diseases. Studies show that patients often refuse regular injections for peptide drugs, particularly when a disease is in its initial stages. Recently, there have been significant advances in the oral delivery of key peptide drugs, including popular GLP-1 analogs like semaglutide. Notably, FDA-approved oral formulations of these drugs, made possible by co-formulating peptides with permeation enhancers, are beginning to change how peptide drugs are administered orally. Thanks to these permeation enhancers, it is now possible to take relatively long, linear peptides orally — something that was mostly impossible before. However, many challenges still exist with the current permeation-enhancer-based delivery systems.
Firstly, the oral bioavailability of these complex absorption processes remains quite low, often less than 1%. Therefore, structure-guided improvements—such as rationally modifying peptide sequences to enhance permeation with permeation enhancers—are urgently needed to boost absorption and reduce the amount of permeation enhancer required. Second, the specific molecular mechanisms by which permeation enhancers allow relatively long, polar peptides like semaglutide to cross epithelial barriers are still largely unknown. To advance this field, this presentation will highlight our recent work,1 which provides, for the first time, a detailed and plausible molecular mechanism explaining how a polar peptide like semaglutide can realistically pass through a membrane with the help of salcaprozate sodium (SNAC), the permeation enhancer used in Rybelsus (the FDA-approved oral formulation of semaglutide). I will present both simulation results, obtained through scalable continuous constant pH molecular dynamics (CpHMD) simulations, and experimental evidence (NMR, DOSY, and DLS) to support this unique permeation mechanism. Our combined data indicate the formation of permeation-enhancer-filled fluid membrane defects, where the polar peptide becomes embedded inside the epithelial membrane, similar to sinking in quicksand. Based on this new mechanistic understanding, our laboratory is actively working to refine peptide formulations further, aiming to improve oral bioavailability while simultaneously reducing the amount of permeation enhancers required.