Identification of Cyclic Peptide Antagonists of an Anti-Opioid G Protein-Coupled Receptor

抗阿片G蛋白偶联受体环肽拮抗剂的鉴定

基本信息

批准号：
10256110
负责人：
Sid Ahmed Labed
金额：
$ 25.51万
依托单位：
EVODENOVO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10256110
关键词：
Absence of pain sensation Address Adverse effects Agonist American Analgesics Animal Model Bacteria Behavior Behavioral Biological Assay Biological Models Brain region Bypass Caenorhabditis elegans Cell Membrane Permeability Chronic Clinical Trials Complex Coupled Cyclic Peptides Cyclization Dependence Detection Development Divorce Drug Prescriptions Eligibility Determination Engineering Escherichia coli Evaluation Event FDA approved Family Florida Foundations G-Protein-Coupled Receptors Goals Government Habenula Health Human Hydrolysis Institutes Investigation Knock-out Knockout Mice Lead Libraries Locomotion Mammalian Cell Mammals Medial Modeling Morphine Movement Mus Nematoda Neurons Opioid Opioid Analgesics Opioid Receptor Orphan Outcome Pain Pain management Peptides Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Physiological Positioning Attribute Predisposition Property Receptor Signaling Recombinants Research Institute Rewards Safety Signal Transduction Small Business Innovation Research Grant System Technology Testing Therapeutic Time Validation Withdrawal abuse liability antagonist base clinically relevant clinically significant cost design drug discovery experimental study feeding follow-up high throughput screening in vivo industry partner inhibitor innovation locus ceruleus structure member mu opioid receptors neural circuit neurotoxicity novel opioid overdose opioid use disorder peptide drug receptor recombinant peptide screening side effect small molecule therapeutic candidate therapeutically effective trafficking tv watching

项目摘要

Identification of Cyclic Peptide Antagonists of an Anti-Opioid G Protein-Coupled Receptor RFA-DA-19-019 R43 Phase I SBIR PI: Sid A. labed Project Summary The highly addictive properties of opioid drugs, coupled with routine over-prescription, have resulted in a national crisis. Accidental overdose by opioids has increased over 400% in the last 15 years, from ~8,000 opioid- related overdoses to more than 30,000 in 2015. The staggering cost of the opioid health crisis to the American public exceeds $50 billion annually, highlighting the need for safer therapeutics for pain management. Drs. Kirill Martemyanov and Brock Grill at the Scripps Institute, Florida, have engineered a model system expressing a functional mammalian opioid receptor (MOR) in the model nematode Caenorhabditis elegans for discovery of opioid modulators. Using this system, they identified an orphan G Protein Coupled Receptor, GPR139, as a negative regulator of MOR signaling. In mammals, GPR139 is co-expressed with MOR in opioid-sensitive brain regions and influences MOR trafficking and signaling. Deletion of GPR139 in mice enhanced opioid-induced inhibition of neuronal firing, increased the analgesic and rewarding effects of morphine, and reduced withdrawal. Previous efforts to target GPR139, which have largely focused on identification of small molecule agonists, has failed to produce a therapeutic candidate antagonist with favorable pharmacological properties. To address this unmet need, EvoDenovo will screen an innovative library of cyclic peptides (CPs) for new GPR139 antagonists by combining two state-of-the-art C. elegans technologies exclusive to EvoDenovo: 1) InVivo Display: a high-throughput screening technology invented by EvoDenovo that can be used for peptide-based drug discovery that bypasses the necessity of peptide purification by directly feeding live recombinant E. coli clones, each expressing a different cyclic peptide, directly to nematodes expressing mammalian MOR and human GP139. This drastically reduces the cost and time for screening. 2) The anti-opioid behavior platform developed at Scripps by Drs. Martemyanov and Gril that assesses the behavioral effects of opioids and identifies pharmacological outcomes of different drugs. The combination of both platforms, assisted by an automated C. elegans movement tracking system, will yield a powerful high throughput screening engine capable of interrogating thousands of recombinant peptides within a few days, all in a unique in vivo setup. GPR139 antagonists identified using this assay would likely be missed by conventional screening protocols. EvoDenovo uses CPs instead of linear peptides. The cyclization of peptides increases gut stability by eliminating vulnerable N- and C-termini, reduces susceptibility to proteolytic hydrolysis, and enhances membrane permeability. There are 2 specific aims: Aim 1: Perform a behavioral screen for cyclic peptide antagonists of GPR139 in C. elegans. Aim 2: Validate hits generated from the C. elegans platform in mammalian cell-based assays. This Phase I proposal will provide the foundation for a Phase II SBIR which will include a larger-scale screen and follow-up on prioritizing CP hits, mammalian testing, and IND enabling studies. EvoDenovo RFA-DA-19-019/ PI: Sid A. Labed Project Summary - Page 1 of 1

鉴定抗阿片类G蛋白偶联受体的环状肽拮抗剂 RFA-DA-19-019 R43 I期SBIR pi：sid A. 项目摘要阿片类药物的高度上瘾的特性，再加上常规的过度处方，导致了国家危机。在过去的15年中，阿片类药物的意外过量服用超过400％，从约8,000个阿片类药物增加相关的过量服用到2015年超过30,000。阿片类药物健康危机的惊人成本公众每年超过500亿美元，强调了对疼痛管理更安全的治疗剂的需求。博士。基里尔佛罗里达州斯克里普斯研究所的Martemyanov和Brock Grill已经设计了一种模型系统，表达了模型线虫秀丽隐杆线虫中的功能性哺乳动物阿片受体（MOR）用于发现阿片类药物调节剂。他们使用此系统将孤儿G蛋白偶联受体GPR139确定为A MOR信号的负调节器。在哺乳动物中，GPR139与阿片类药物敏感大脑中的MOR共表达区域并影响MOR贩运和信号传导。在小鼠中删除GPR139 抑制神经元放电，增加吗啡的镇痛和有益作用，并减少了戒断。以前旨在针对GPR139的努力，这些GPR139在很大程度上集中于鉴定小分子激动剂，未能产生具有良好药理特性的治疗候选拮抗剂。解决这种未满足的需求，Evodenovo将筛选新GPR139的创新循环肽库（CPS）通过将两种最先进的C.秀丽隐杆线虫技术组合为Evodenovo的对抗者：1）Invivo 显示：Evodenovo发明的高通量筛选技术可用于基于肽的通过直接喂养活体重组大肠杆菌，绕过肽纯化的必要性的药物发现克隆，每个克隆都表达不同的环状肽，直接向表达哺乳动物MOR和的线虫人类GP139。这大大减少了筛选的成本和时间。 2）抗阿片类行为平台 Drs在Scripps开发。 Martemyanov和Gril评估阿片类药物的行为影响并确定不同药物的药理结果。两个平台的组合，在自动化的C. 秀丽隐杆线运动跟踪系统将产生强大的高通量筛选引擎在几天之内询问数千种重组肽，所有这些肽都以独特的体内设置进行。 GPR139 常规筛选方案可能会错过使用此测定法确定的拮抗剂。 Evodenovo 使用CP而不是线性肽。肽的环化通过消除脆弱的人来提高肠道稳定性 N-和C-termini，可降低对蛋白水解水解的敏感性，并增强膜渗透性。有2个特定目的：目标1：对GPR139的环状肽拮抗剂进行行为屏幕秀丽隐杆线。 AIM 2：在基于哺乳动物细胞的测定中从秀丽隐杆线虫平台产生的验证点击。这第一阶段的提案将为II期SBIR提供基础，其中包括大型屏幕和对CP命中，哺乳动物测试和IND启用研究的优先级进行后续措施。 Evodenovo RFA-DA-19-019/ PI：SID A. Labed Project摘要 - 第1页，共1页