09.10.2024
Engineering Nav1.7-specific nanobodies
The voltage-gated sodium channel Nav1.7 plays a critical role in transmitting pain signals in nociceptive neurons. Genetic mutations in Nav1.7 can lead to various pain disorders, including extreme pain conditions and congenital insensitivity to pain. Despite its importance, targeting Nav1.7 for pain treatment has proven difficult due to its structural similarity with other sodium channel subtypes, which limits the effectiveness of small molecules and monoclonal antibodies.
In a recent study, researchers developed a novel antigen design strategy to generate single-domain antibodies (VHHs) that specifically target the Nav1.7 channel. They selected a unique extracellular loop from Nav1.7 as the target antigen (a region of 70 amino-acid residues from the domain DI extracellular loop 3) and grafted it into the complementarity-determining region 3 (CDR3) loop of an inert llama VHH to stabilize the native 3D conformation of this DIE3IR loop in the absence of the rest of the hNav1.7 channel. The resulting recombinant protein was then used to isolate VHHs specific to the DIE3 loop. This approach enabled the production of VHHs capable of binding to Nav1.7 with high specificity and functional efficacy.
The team employed several techniques, including molecular modeling, phage display, and electrophysiological assays using the high-throughput automated patch-clamp system SyncroPatch, to isolate and characterize VHHs with the desired properties. Among the identified candidates, VHH DI-D was shown to slow the deactivation kinetics of Nav1.7, reduce the firing of action potentials in pain-sensing neurons, and reverse hyperalgesia in rat and mouse models of pain.
These findings highlight the potential of this new antigen design strategy to develop highly specific biologics for targeting ion channels, transporters, and GPCRs.
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Find the full article here: A Novel Antigen Design Strategy to Isolate Single-Domain Antibodies that Target Human Nav1.7 and Reduce Pain in Animal Models
Learn more about the SyncroPatch 384, our newest generation automated patch clamp system: https://www.nanion.de/products/syncropatch-384/