Planning Study for the Development of Sigma 2 ligands as Analgesics

项目摘要 迫切需要开发针对慢性疼痛的新靶点的新型治疗剂。这 一项提案将使用蓝细菌衍生的天然产物作为慢性神经性疼痛药物的起点 通过靶向σ 2/跨膜蛋白97（σ-2/TMEM97）进行开发。σ-2/TMEM97受体 已经被发现超过40年，但直到2017年才有分子身份及其 在疼痛中的潜在作用被描述。利用新的晶体结构σ-2/TMEM97和五项描述 σ-2/TMEM97调节剂治疗啮齿动物疼痛的潜力，这将是一个快速探索的领域， 未来几年的发展。我们的初步数据显示，我们的天然产物对σ- 2/TMEM 97以及早期暗示体外调节人类“伤害感受器”的可能性机制 在原代小鼠背根神经节神经元中鉴定的作用。我们已经建立并将继续扩大 并在此规划建议中加强互补的生物和化学团队，为我们做好准备， 成功过渡到项目的U19阶段。这些团队由多元化和跨学科的 一群科学家和利益相关者以及与学术药物发现中心和 商业计算筛选组。我们的技术办公室将确保强大的知识产权 保护整个项目和商业和创业顾问将帮助团队发展 商业开发计划是可行的，并保持关键目标产品概况的细节作为驱动力， 该项目总体而言，这一建议将产生i）一个强大的，综合的，多样化的，多学科的研究团队 ii）针对物理化学性质和理论结合筛选的潜在类似物的计算机模拟文库 得分导致iii）5-10种合成化合物的体外功效和实验药物样活性 特性.这些先导化合物和该团队产生的数据将构成我们U19的基础 建议将我们的前1-3名候选人转移到诊所。

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.