TRPV1 antagonism occurs through diverse structural mechanisms

Area of Science:

• Structural biology
• Ion channel research
• Pharmacology

Background:

• Transient receptor potential vanilloid 1 (TRPV1) is crucial for thermosensation and pain, making it a key target for non-addictive analgesics.
• Clinical TRPV1 antagonist candidates have faced setbacks due to thermoregulatory side effects, highlighting a need for better mechanistic understanding.

Purpose of the Study:

• To elucidate the structural basis of human TRPV1 (hTRPV1) antagonism using diverse chemotypes.
• To provide mechanistic insights into why clinical TRPV1 antagonists have failed and to inform the design of safer analgesics.

Main Methods:

• Chemoinformatics-informed cryo-electron microscopy (cryo-EM) and bioluminescence resonance energy transfer (BRET) assays were employed.
• Structures of hTRPV1 were determined in complex with various antagonists, including 6-iodo-dihydrocapsaicin, Asivatrep, Mavatrep, and JNJ-17203212.

Main Results:

• Structural data revealed how a single substitution can convert a TRPV1 agonist into an antagonist.
• Vanilloid pocket plasticity and divergent interaction networks, including lipid co-binding, were observed across different antagonists.
• Despite diverse binding modes, all antagonists converged on a conserved inhibited state, maintaining high potency.

Conclusions:

• The findings redefine the understanding of hTRPV1 antagonism, highlighting conserved inhibitory mechanisms.
• Chemically diverse ligands can stabilize an inhibited state in polymodal ion channels like TRPV1.
• This work lays the foundation for developing next-generation analgesics with improved safety profiles by targeting TRPV1 effectively.