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Discovery of PSD95 protein-protein interaction inhibitors as novel non-opioid analgesics

发现 PSD95 蛋白质-蛋白质相互作用抑制剂作为新型非阿片类镇痛药

基本信息

批准号：
10569221
负责人：
STEPHANIE K FLORIO
金额：
$ 96.25万
依托单位：
ANAGIN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569221
关键词：
Address Adverse effects Adverse reactions Affect American Analgesics Animal Model Antiepileptic Agents Behavioral Behavioral Model Biological Biological Assay Brain Canis familiaris Cells Central Nervous System Diseases Chemicals Chromosome abnormality Clinic Clinical Clinical Trials Complex Data Development Dose Drug Targeting Exhibits Funding Glucuronides Glutamates Health Healthcare Systems Hepatotoxicity In Vitro Lead Lesion Life Literature Maintenance Mediating Membrane N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor antagonist Nerve Degeneration Neuraxis Neurons Nitric Oxide Synthase Type I No-Observed-Adverse-Effect Level Non-Steroidal Anti-Inflammatory Agents Opiate Addiction Opioid Oral Pain Pathologic Pathologic Processes Pathway interactions Peptides Persons Pharmaceutical Preparations Pharmacotherapy Phase Post-Traumatic Stress Disorders Pre-Clinical Model Process Property Proteins Publishing Rattus Receptor Activation Receptor Signaling Research Personnel Risk Safety Scaffolding Protein Series Signal Pathway Signal Transduction Small Business Innovation Research Grant Specificity Steroids Stroke Testing Therapeutic Therapeutic Index Toxic effect Toxicology Traumatic Brain Injury Triage United States Validation Work addiction addiction liability analog antagonist central sensitization chronic neuropathic pain chronic pain clinical candidate cost estimate design experience functional group gabapentin genotoxicity good laboratory practice hazard health care availability high risk improved in vitro Assay in vivo ineffective therapies inhibitor lead optimization neural network neuron loss neuropsychiatry non-opioid analgesic novel novel therapeutics opioid epidemic pain model painful neuropathy patient subsets phase 1 study postsynaptic density protein pre-clinical pregabalin protein protein interaction receptor receptor binding recruit respiratory safety study side effect small molecule socioeconomics stroke model tool

项目摘要

Project Summary This application, “Discovery of PSD95 protein-protein interaction inhibitors as novel non-opioid analgesics”, addresses the critical need for more effective medications to treat chronic neuropathic pain. Pain is responsible for more encounters with the health care system than any other single cause, yet treatment options for neuropathic pain have limited efficacy and carry a high risk for side effects, including opioid addiction. These factors add an additional $560-635 billion annually to an already strained United States health care system. Glutamate activation of N-methyl-D-aspartate (NMDA) receptors mediates central nervous system (CNS) sensitization, which is implicated in the development and maintenance of neuropathic pain. NMDA-mediated central sensitization depends on formation of a multi-protein cascade complex at the receptor consisting of the NMDA receptor bound to the scaffolding protein, postsynaptic density protein 95 (PSD95), and recruitment of neuronal nitric oxide synthase (nNOS). By bringing these proteins close together, multiple signaling cascades are activated leading to neural network reorganization (plasticity) and neuronal cell death. Small molecules and cell penetrating peptides that disrupt this complex act as effective analgesics in preclinical animal models with better side effect profiles than non-selective NMDA receptor antagonists and NOS inhibitors. Our team, the first to publish a small molecule targeting this complex, IC87201, demonstrated its efficacy in preclinical pain models. A similar small molecule, ZL006, is effective in preclinical stroke models. We designed and synthesized a unique and novel set of IC87201 and ZL006 analogs, advancing one molecule into IND-enabling studies for post- traumatic stress disorder. After identifying concerns with the candidate molecule, we systematically redesigned it resulting in a new set of molecules. Further funding is needed to improve on these molecules prior to advancing them toward new IND-enabling studies. Importantly, advanced toxicology studies with the candidate molecule suggest a low risk of target specific side effects and predict an excellent therapeutic index for compounds with acceptable activity and drug-like properties. In this SBIR Phase I/II fast track application, Anagin, in concert with our collaborators and the Blueprint Neurotherapeutics Network, will design and test molecules for improved drug- like properties, confirm target engagement in in vitro and ex vivo assays, demonstrate efficacy in preclinical pain models and establish a therapeutic margin using behavioral models. We will advance a new clinical candidate molecule through IND-enabling studies. Compounds that do not meet our set criteria will not be advanced. At the conclusion of these studies, we will have a new clinical candidate thoroughly interrogated and poised for testing in clinical trials for chronic pain. Data summarized in this proposal strongly suggests that our approach will yield effective analgesics with better therapeutic indices than other compounds in development or the clinic. These compounds are likely to be useful in many other glutamate-driven CNS diseases.

项目总结