Chronic pain remains a leading cause of disability worldwide, yet there are few effective and safe pharmacological options for long-term management. The voltage-gated sodium channel NaV1.7, a key mediator of pain signal transmission, has emerged as a promising target for next-generation analgesics. Unlike opioids, NaV1.7-targeted agents have the potential to block pain at its source without engaging central pathways, thereby reducing the risks of addiction, tolerance, and respiratory depression. However, the development of selective NaV1.7 inhibitors has been hindered by challenges in achieving sufficient specificity and avoiding off-target effects on other sodium channel subtypes critical for cardiac and skeletal muscle function.
Despite strong evidence of in vitro efficacy of NaV1.7 inhibitors in suppressing nociceptor excitability, translation to in vivo models and clinical settings has been limited. Many compounds fail to produce meaningful analgesia due to incomplete channel blockade in complex tissues and compensatory mechanisms that maintain pain signalling. These limitations underscore the need for innovative approaches to achieve robust and physiologically relevant inhibition of NaV1.7 in vivo.
To address these challenges, we developed a novel bitopic ligand combining venom-derived NaV1.7 modulating peptides. Unlike earlier bitopic designs, which showed limited efficacy in vitro and negligible improvements over monovalent ligands, our compound exhibits synergistic inhibitory activity. This bitopic ligand demonstrates a 145-fold increase in potency compared to a mixture of the individual monovalent components and effectively blocks NaV1.7-specific pain in vivo. These findings highlight a promising strategy for overcoming the translational barriers that have impeded NaV1.7-targeted pain therapeutics.