Kevin Tidgewell Scope:COBRE in Pharmaceutical Research and Innovation

There is a pressing need to develop novel therapeutic agents against new targets for chronic pain. This project will use cyanobacterial-derived natural products as the starting point for chronic neuropathic pain drug development by targeting the sigma 2/transmembrane protein 97 (σ-2/TMEM97) receptor and other targets involved in pain. The σ-2/TMEM97 receptor has been pharmacologically known for over 40 years but only since 2017 has the molecular identity and its possible role in pain been described. With a new crystal structure σ-2/TMEM97 and five studies describing the potential of σ-2/TMEM97 modulators to treat pain in rodents, this will be an area of rapid exploration and development in the coming years. Our preliminary data show selectivity of proof-of-concept cyanobacterial natural products for σ-2/TMEM97 as well as data showing analgesic effects in mice with potential to modulate human “nociceptors” in vitro with mechanisms of action identified in primary mouse dorsal root ganglion neurons. Loss of σ-2/TMEM97 leads to enhanced recovery from inflammatory pain suggesting a normally pro-nociceptive role of σ-2/TMEM97. Using existing (139 hits for σ-2/TMEM97) and new compounds isolated from cyanobacteria, this project will yield i) a cyanobacterial natural products library of σ-2/TMEM97 ligands with well-defined binding and functional characterization and ii) improved understanding of the pharmacological and biological role of σ-2/TMEM97 in human nociceptors. The best lead compounds and data generated from this proposal will then form the basis of future proposals to better understand and manipulate the σ-2/TMEM97 system for the treatment of neuropathic pain.