G-protein-coupled receptors (GPCRs) have key roles in physiology and are central targets for drug discovery and development[1,2], but the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic[3-6]. Here we describe de novo design methods and a high-throughput receptor-diversion microscopy-based screen for generating GPCR-binding miniproteins with high affinity, potency and selectivity. We design miniprotein agonists that activate receptors involved in itch and pain, as well as antagonists that inhibit receptors implicated in cancer, metabolic disorders such as diabetes and obesity, and migraines. The cryo-electron microscopy (cryo-EM) structures of five receptor-bound designs are close to the computational design models. A designed chemokine receptor antagonist mobilizes haematopoietic stem and progenitor cells in vivo at a level comparable to a clinically used drug, with fewer adverse effects.

Itch is an aversive sensory experience inextricably linked to a desire to scratch.[1][,][2] While recent progress has advanced our understanding of itch sensation and transmission, the neural mechanisms underlying how scratching is sensed and controlled remain largely elusive. Here, we show that the left lateral habenula (LHb), which responds to negatively valent somatosensory stimuli,[3][,][4][,][5][,][6][,][7][,][8] preferentially engages and negatively regulates chloroquine (CQ)-evoked itch and scratching. Calcium activity in left LHb neurons increases when scratching is terminated, and their activation is sufficient to suppress itch-evoked scratching in an intensity-dependent manner. Peripheral MrgprD[+] C-fiber afferents and PIEZO2 are required for scratching-evoked LHb activation and its suppression of scratching behaviors. Collectively, this work establishes a pathway that controls itch-evoked scratching from the periphery to the brain and reveals a novel left-right asymmetry of mammalian LHb functionality.

A priority setting partnership for eczema (syn atopic eczema, atopic dermatitis) has identified that bathing frequency is a key area of patient interest. However, there are nolarge, high-quality randomised controlled trials (RCTs) investigating this.The Rapid Eczema Trials project is a novel programme of research that aims to deliver multiple online RCTs, using a citizen science approach. This project involves working with members of the public to co-design and conduct studies that answer questions of importance to them. The first trial to be conducted through this project is assessing the impact of bathing frequency on eczema.

Recessive dystrophic epidermolysis bullosa (RDEB) is a skin fragility disorder characterised by life-long mechanically induced skin blistering, fibrosis-driven pseudosyndactyly, and multi-organ involvement. Preclinical studies have suggested mitigated progression by angiotensin II type I receptor blockade through losartan. We aimed to determine the safety and tolerability of systemic losartan treatment among children with RDEB, and to obtain initial data on its clinical benefit.