Researchers have identified a mini antibody that blocks signaling by a disease-related ion channel protein potently and selectively. When the P2X7 channel senses ATP from damaged cells, it sends signals that can lead to conditions such as nerve inflammation, multiple sclerosis, and rheumatoid arthritis. Several drug companies are developing small-molecule P2X7 inhibitors, but the agents have had poor target selectivity, a factor that can cause side effects. Friedrich Koch-Nolte of University Medical Center Hamburg-Eppendorf and coworkers have now identified a minimal antigen-binding domain, called a Nanobody, that selectively inhibits human P2X7 (Sci. Transl. Med. 2016, DOI: 10.1126/scitranslmed.aaf8463). In endotoxin-treated human blood, the Nanobody was 1,000 times as potent at preventing cytokine release, a harbinger of inflammation, as small-molecule P2X7 antagonists in clinical development. Nanobodies are often species-specific, making animal testing difficult, and they tend to have trouble crossing the blood-brain barrier, which could limit their use for neurological indications, comments P2X7 expert Ronald Sluyter of the University of Wollongong. Nevertheless, the new study does suggest that Nanobodies “provide an exciting, novel therapeutic approach to targets P2X7,” Sluyter says.