Peptide Permeation Across Lipid Membranes: Designing Peptides and Formulations Through Structure-Activity Relationships

In the realm of peptide R&D, the design of drug products capable of enhanced delivery through lipid membranes stands at the forefront of innovation. A substantial portion of peptide therapeutics necessitates interaction with cellular membranes to achieve their desired therapeutic effects. Strategies to enhance membrane permeation often involve either augmenting the intrinsic permeability of the peptide molecules, combining therapeutic and cell-penetrating capabilities, or incorporating permeation enhancers into formulations to modulate the translocation pathway. Understanding the molecular mechanisms underpinning cellular affinity and permeability is thus critical for the development of structure-activity relationships at the residue level in the design of peptide drug and formulation. A notable gap exists in our comprehension of the molecular interactions and translocation processes through lipid bilayers, which are crucial for identifying the structural motifs that govern membrane affinity and translocation. This study elucidates the structural and dynamic behaviors underlying the interaction of preclinical peptide drugs with lipid bilayers. Our combined experimental and computational modeling approaches offer a detailed in silico perspective on the migration of peptides from the external to the internal layers of the membrane. These findings underscore the significance of peptide-lipid interactions and dynamics in enabling peptides to traverse membranes—a process critical for drugs designed with cell-penetrating capabilities. Furthermore, our application of advanced structural biophysical techniques has shed light on how peptides, aided by permeation enhancers, navigate through the lipid membrane. Through quantitative analysis, we have successfully determined how permeation enhancers (PEs) modify the molecular dynamics of lipids to support peptide insertion. The insights gained from examining the interactions and interplay between peptides, PEs, and lipids offer structural rationales for the development of innovative PEs and formulations, aiming to enhance the delivery of peptide drugs.