Membrane proteins play vital roles in cell signaling, molecular transportation, and cell adhesion. The interactions of transmembrane domains are much less well understood than those of their water-soluble counterparts, and they have been deemed “undruggable” despite their important biological functions such as protein anchoring, signal transduction, and ligand recognition. Nevertheless, continual developments in this area have revealed useful probes for investigating and regulating these membrane proteins. This review summarizes and evaluates the strategies available for discovering small molecules and peptides that recognize the protein transmembrane domains of membrane proteins, with a particular focus on rational design and library screening.

Neuroinflammation has been conceived as an important cause for or contributor to neurological diseases. With major strides in new technology, scientists can use chemical biology tools developed in non-neuronal systems to research neuroinflammation. Extracellular vesicles (EVs) play a vital role in mediating neuroinflammation via carrying pathogenic misfolded proteins as well as nucleic acids, suggesting important biological functions. Nonetheless, it is a daunting goal to study these ultramicroscopic EVs in part due to the technical hurdle of specific labeling and preparation. Therefore, development of new detection methods of EVs will promote further understanding of EVs in the nervous system, thereby expediting the diagnosis and therapy development for neurological disorders. Recent progress toward a new class of chemical biology probes simultaneously targeting the highly curved surface and the particular lipid compositions of EVs may offer an alternative strategy for their detection, isolation, and purification, which not only will facilitate research on their mechanism in neuroinflammation and neurological diseases, but also may lay the groundwork for the next generation of diagnostics and prognostics.Keywords: detection technology; drug discovery; extracellular vesicles; lipidomics; membrane curvature; Neuroinflammation