Skape Bio and UW Medicine researchers reported AI-designed miniproteins that can selectively activate or block multiple GPCR targets—addressing a core drug-discovery bottleneck for receptors whose accessible regions can be limited. The work, published in Nature, describes a design pipeline validated with cryo-EM structures and functional assays. The study reported miniprotein designs spanning 11 GPCRs across receptor families, including examples targeting deep or flexible pockets. Agonist validation included multiple targets tied to itch and pain, while other designs focused on receptor classes implicated in cancer, metabolic disease, and migraine. For development teams, the reported ability to design functional miniproteins from scratch—tied to structural validation—strengthens the case for computational protein design as a route into “undruggable” GPCR states and pocket conformations.