Planning Study for the Development of Sigma 2 ligands as Analgesics

Sigma 2 配体镇痛药开发规划研究

• 批准号: 10641500
• 负责人: BENEDICT J KOLBER
• 金额: $ 151.01万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-11 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641500
• 关键词: Affinity; Analgesics; Area; Basic Science; Behavior; Binding; Binding Sites; Biological; Biology; Businesses; C-terminal; Cells; Chemicals; Chemistry; Clinic; Collaborations; Communities; Computational Technique; Data; Development; Development Plans; Docking; Dose; Endoplasmic Reticulum; Ensure; Evaluation; Exhibits; Female; Goals; Grant; Human; Hypersensitivity; In Vitro; Industrialization; Industry; Integral Membrane Protein; Intellectual Property; Interdisciplinary Study; Investigation; Knockout Mice; Lead; Libraries; Ligands; Mechanics; Methodology; Methods; Modeling; Modernization; Modification; Molecular; Molecular Analysis; Molecular Computations; Mus; N-terminal; Natural Products; Neurons; Nociceptors; Pain; Patients; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Process; Property; Psychotropic Drugs; Publishing; Research Personnel; Rodent; Role; Scientist; Series; Signal Transduction; Specialist; Specificity; Spinal Ganglia; Structure; Suggestion; Symptoms; Technology; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Work; analog; chemical property; chronic neuropathic pain; chronic pain; clinical practice; cytotoxicity; design; driving force; drug development; drug discovery; drug-like compound; improved; in silico; induced pluripotent stem cell; male; marine; molecular modeling; multi-electrode arrays; nerve injury; neuroinflammation; neuroprotection; non-opioid analgesic; novel; novel strategies; novel therapeutics; pain reduction; pain relief; painful neuropathy; pharmacokinetics and pharmacodynamics; pharmacologic; prospective; receptor; research and development; screening; screening program; sigma-2 receptor; spared nerve; success; therapy outcome

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.

项目摘要 迫切需要开发针对慢性疼痛的新靶标的新型热剂。这 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Sigma 2/跨膜蛋白97（σ-2/TMEM97）的开发。 σ-2/TMEM97接收器 在物理上闻名已有40多年了，但自2017年以来才具有分子身份及其 描述了疼痛中的潜在作用。使用新的晶体结构σ-2/TMEM97和五项描述的研究 σ-2/TMEM97调节剂的潜力治疗啮齿动物的疼痛，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了我们对σ-的天然产物的选择性 2/tmem97以及可能在体外调节人类“伤害感受器”的潜力的早期建议 在原代小鼠背根神经元中鉴定出的作用。我们已经建立并将继续扩展 以及在计划提案中，强大的互补生物学和化学团队为我们做好准备 成功过渡到项目的U19阶段。这些团队由潜水员和跨学科组成 科学家和利益相关者组以及与学术药物发现中心的合作伙伴关系 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 在整个项目，业务和企业家顾问中的保护将帮助团队发展 可行的商业开发计划，并将关键目标产品概况详细信息作为驱动力 项目。总体而言，该建议将产生i）一个强大，综合，潜水和多学科研究团队 ii）筛选物理特性和理论结合的潜在类似物的内部库库 导致III的评分）5-10种合成化合物，以评估体外效率和实验性药物样的分数 特性。这些团队生成的这些铅化合物和数据将构成我们的U19的基础 提议将我们的前1-3名候选人转移到诊所。