Structural Dynamics of GLP-1 Analogues: Folding Energetics, Lipidation-Driven Assembly, and Aggregation Mechanisms.

Glucagon-like peptide-1 (GLP-1) analogues are a major class of peptide therapeutics used to treat metabolic diseases. GLP-1-derived peptides are characterized by dynamic conformational ensembles in which folding, intermolecular assembly, and aggregation are strictly coupled processes. This study focused on the effects of sequence modifications, such as helix-promoting residues and backbone constraints on the helix-coil equilibrium, as well as lipidation, which creates competing equilibria among monomeric, oligomeric, and albumin-bound forms. These coupled equilibria simultaneously enhance pharmacokinetic properties and modulate conformational stability. We also explored how environmental conditions such as ionic concentration and temperature affect conformation, and emphasize how manufacturing processes act as external perturbations that could impact structural integrity. Moreover, we focus on the increasingly emerging new multi-agonist peptides, noting that their increased sequence complexity broadens conformational diversity and poses challenges to existing design methods. Despite significant experimental progress, predictive models capable of mapping the intricate interconnections among peptide sequences, lipidation patterns, and aggregation pathways remain critically limited. This highlights the importance of integrating biophysics, computation, and process science. The review points out that designing effective GLP-1 therapeutics rationally depends on managing conformational distributions across complex energy landscapes, not just stabilizing individual structures, in order to offer a new framework for developing the next generation of peptide drugs.