Human TRPV1 structure and inhibition by the analgesic SB-366791

Arthur Neuberger, Mai Oda, Yury A. Nikolaev, Kirill D. Nadezhdin, Elena O. Gracheva, Sviatoslav N. Bagriantsev and Alexander I. Sobolevsky ()
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Arthur Neuberger: Columbia University
Mai Oda: Yale University School of Medicine
Yury A. Nikolaev: Yale University School of Medicine
Kirill D. Nadezhdin: Columbia University
Elena O. Gracheva: Yale University School of Medicine
Sviatoslav N. Bagriantsev: Yale University School of Medicine
Alexander I. Sobolevsky: Columbia University

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract Pain therapy has remained conceptually stagnant since the opioid crisis, which highlighted the dangers of treating pain with opioids. An alternative addiction-free strategy to conventional painkiller-based treatment is targeting receptors at the origin of the pain pathway, such as transient receptor potential (TRP) ion channels. Thus, a founding member of the vanilloid subfamily of TRP channels, TRPV1, represents one of the most sought-after pain therapy targets. The need for selective TRPV1 inhibitors extends beyond pain treatment, to other diseases associated with this channel, including psychiatric disorders. Here we report the cryo-electron microscopy structures of human TRPV1 in the apo state and in complex with the TRPV1-specific nanomolar-affinity analgesic antagonist SB-366791. SB-366791 binds to the vanilloid site and acts as an allosteric hTRPV1 inhibitor. SB-366791 binding site is supported by mutagenesis combined with electrophysiological recordings and can be further explored to design new drugs targeting TRPV1 in disease conditions.

Date: 2023
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DOI: 10.1038/s41467-023-38162-9

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