Orally available Colivin traps TRPV3 in an inactive state and suppresses intestinal inflammation

Abstract

Transient receptor potential vanilloid 3 (TRPV3) is a non-selective cation channel highly expressed in the skin and intestine. While its roles in itch and skin inflammation are established, the physiological role of TRPV3 in the intestine remains relatively poorly understood. Topical application of a TRPV3 inhibitor, KM-001, has entered phase I clinical trials for the treatment of pruritus; however, its poor metabolic stability limits broader therapeutic application. Here, we show that the KM-001-derivative Colivin has comparable TRPV3-blocking activity, but enhanced metabolic stability and increased oral bioavailability. Cryo-EM and site-directed mutagenesis analyses established that Colivin binds to the vanilloid binding pocket of TRPV3, stabilizing one of two distinct non-conducting conformations. Oral administration of Colivin effectively suppressed DSS-induced ulcerative colitis (UC) in wild-type, but not Trpv3-deficient mice. Collectively, our findings establish TRPV3 inhibition as a novel therapeutic strategy for UC, offer key structural insights into the inhibition mechanism of TRPV3, and provide critical structural insights for the rational design of potent and selective TRPV3 inhibitors. TRPV3 drives itch and inflammation in the skin, but is also widely expressed in the intestine where its function is unclear. This study identifies orally available Colivin as a TRPV3 inhibitor and key regulator of intestinal inflammation, suggesting intestinal TRPV3 inhibition as a promising therapeutic strategy for ulcerative colitis. Colivin, an optimized KM-001 derivative, maintains potent TRPV3 inhibition with enhanced metabolic stability and oral bioavailability. Colivin targets the TRPV3 vanilloid pocket and stabilizes two distinct non-conducting conformations, providing a structural basis for future TRPV3 inhibitor development. Oral Colivin administration effectively reduces DSS-induced ulcerative colitis in wild-type but not Trpv3-/- mice. Colivin, an optimized KM-001 derivative, maintains potent TRPV3 inhibition with enhanced metabolic stability and oral bioavailability. Colivin targets the TRPV3 vanilloid pocket and stabilizes two distinct non-conducting conformations, providing a structural basis for future TRPV3 inhibitor development. Oral Colivin administration effectively reduces DSS-induced ulcerative colitis in wild-type but not Trpv3-/- mice. Structural trapping reveals TRPV3 to be a druggable driver of intestinal inflammation.