TRPV3 in Drug Development

Abstract

Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP (Transient Receptor Potential) super-family. It is a relatively underexplored member of the thermo-TRP sub-family (Figure 1), however, genetic mutations and use of gene knock-outs and selective pharmacological tools are helping to provide insights into its role and therapeutic potential. TRPV3 is highly expressed in skin, where it is implicated in skin physiology and pathophysiology, thermo-sensing and nociception. Gain of function TRPV3 mutations in rodent and man have enabled the role of TRPV3 in skin health and disease to be particularly well defined. Pre-clinical studies provide some rationale to support development of TRPV3 antagonists for therapeutic application for the treatment of inflammatory skin conditions, itch and pain. However, to date, only one compound directed towards block of the TRPV3 receptor (GRC15300) has progressed into clinical trials. Currently, there are no known clinical trials in progress employing a TRPV3 antagonist.

Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field

“…Several companies have pursued selective antagonists of TRPV3 channels including Abbvie (Gomtsyan et al, ), Hydra Biosciences and Glenmark/Sanofi‐Aventis (Grubisha et al, ). The Glenmark/Sanofi‐Aventis compound GRC15300 failed a Phase 2 trial in chronic peripheral neuropathy patients (a 4 week trial), and the collaboration between the two companies was terminated in 2014 (Broad et al, ). However, recent reports suggest that these TRPV3 channel antagonists are not full blockers of the channel (Grubisha et al, ), so it is difficult to know how to interpret these results with regards to a potential role of TRPV3 channels in pain.…”

TRP Channels in Skin Biology and Pathophysiology

“…For example, although published studies are limited, there are reports in the patent literature that TRPV3 antagonists can suppress certain forms of mechanical hypersensitivity in rats after nerve injury [111]. In addition, it was reported that, in the mouse acetone-ether-water model of chronic dry skin, the genetic absence of TRPV3 resulted in reduced scratching behavior [112].…”

Conformational ensemble of the human TRPV3 ion channel

“…These particles (120,424) were then subjected to a no-alignment 3D classification using a soft mask of the full molecule. The best resolving class (27,620 particles) was then 3D auto-refined (C4 symmetry) to a final resolution of 3.4 Å, as estimated by gold-standard FSC 0.143 criterion 62,63 .…”

“…Therefore, TRPV3 plays essential roles in epidermal proliferation, differentiation, survival, hair growth, and the development of itch sensation 26 . Several small-molecule inhibitors of TRPV3 have demonstrated analgesic properties in inflammatory and neuropathic pain models 27,28 .…”