Inhibition of TRPV1 by an antagonist in clinical trials is dependent on cholesterol binding

Abstract

TRP Vanilloid 1 (TRPV1) channel, one of the major members of the TRP family was discovered to play a critical role in pain sensation, particularly inflammatory pain, and is associated with hyperalgesia, an enhanced sensitivity to pain. A new study by Fan et al. “Structural basis of TRPV1 inhibition by SAF312 and cholesterol” sheds new light on the mechanistic structural basis of TRPV1 inhibition by SAF312 (Libvatrep), a TRPV1 antagonist, currently in phase II clinical trials. They discover that the binding site of SAF312 in TRPV1 is in close vicinity and partially overlaps with the binding site of cholesterol and that removal of cholesterol interferes with the ability of SAF312 to suppress TRPV1 current.