Peptide‐Scaffolded Detergents for Membrane Protein Studies

Detergents are essential for preserving the structural integrity and functionality of membrane proteins (MPs) outside the biological membrane or in aqueous solution, and thus ensuring accurate biochemical and structural analyses. Here, we introduce peptide‐scaffolded detergents, a novel class of hybrid molecules formed by preassembling detergent monomers with peptides of varying lengths, mediated via Click chemistry. These detergents are characterized by scalable, straightforward synthesis and enhanced solubility. Among the variants, A4B2 emerged as the optimal detergent, demonstrating superior thermal stabilization across a range of G protein‐coupled receptors, including A2AAR, SMO and GLP‐1R. Additionally, A4B2 exhibits a low critical micelle concentration and small micelle size, together making it particularly effective for electron microscopy studies of A2AAR. This innovative design leverages the benefits of peptide‐based and traditional detergents, offering new insights for the development of advanced detergents in MP research.