PROJECT SUMMARY There is a pressing need to develop novel therapeutic agents against new targets for chronic pain. This proposal 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). The σ-2/TMEM97 receptor has been pharmacologically known for over 40 years but only since 2017 has the molecular identity and its potential 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 our natural products for σ- 2/TMEM97 as well as early suggestions of potential to modulate human “nociceptors” in vitro with mechanisms of action identified in primary mouse dorsal root ganglion neurons. We have built and will continue to expand and strengthen complementary biology and chemistry teams in this planning proposal to prepare us for success in transitioning to a U19 phase of the project. These teams consist of a diverse and interdisciplinary group of scientists and stakeholders as well as partnerships with an academic drug discovery center and a commercial computational screening group. Our technology offices will ensure strong intellectual property protection throughout the project and business and entrepreneurial consultants will help the teams develop commercial development plans that are feasible and keep key target product profile details as driving forces of the project. Overall, this proposal will yield i) a strong, integrated, diverse, and multi-disciplinary research team ii) an in-silico library of potential analogs screened for physicochemical properties and theoretical binding scores resulting in iii) 5-10 synthetic compounds to be evaluated for in vitro efficacy and experimental drug-like properties. These lead compounds and data generated from this team will then form the basis of our U19 proposal to move our top 1-3 candidates towards the clinic.

PROJECT NARRATIVE The proposed planning grant is focused on building a team and conducting preliminary investigations into developing of a new series of natural product analogs designed to target a novel target for non-opioid pain relief, Sigma2 (σ-2) a.k.a. Transmembrane Protein 97 (TMEM97). We have brought together a diverse team of scientists, academic drug discovery specialists, industry specialists, and stakeholders to start our biology and chemistry teams who will work together to progress the development of σ-2/TMEM97 analogs for the treatment of neuropathic pain.