BPS2026 – TRPV1 antagonism occurs through diverse structural mechanisms

Chronic pain affects over 60 million adults in the US and is commonly treated with opioids. Opioids are highly addictive and lead to other unwanted outcomes such as overdose; therefore, alternative pain treatment targets are sought after. The transient receptor potential vanilloid 1 (TRPV1) ion channel plays a role in pain signaling and temperature sensing; however, many small molecules designed to target TRPV1 fail in clinical trials due to issues with core body temperature regulation and thermosensation. To understand the mechanism behind TRPV1 modulation, we combine high-resolution cryo-EM structures with solution NMR and functional cellular assays to investigate how diverse antagonists engage the human TRPV1 vanilloid binding pocket. Our results reveal how subtle chemical modifications to ligands transform an agonist into an antagonist, and that TRPV1 accommodates ligands through conformational plasticity of the vanilloid pocket. We further identify distinct binding poses among chemically diverse antagonists and highlight multiple non-canonical strategies by which antagonism is achieved. These findings expand our understanding of TRPV1 inhibition and provide a framework for designing effective TRPV1-targeting analgesics.