权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Triagonist Peptide Therapeutics for Neuroprotection

用于神经保护的三角肽疗法

基本信息

批准号：
10326283
负责人：
KRISHNA KUMAR
金额：
$ 25.96万
依托单位：
VELUM, INC.
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：
2021-09-25 至 2023-09-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326283
关键词：
Acute Agonist Agreement Alzheimer&apos s Disease American Animal Experiments Animal Model Attenuated Behavioral Biological Assay Biological Process Blood Blood - brain barrier anatomy Blood Glucose Brain Brain Concussion Cell Death Cell model Cells Characteristics Chemicals Chronic Clinical Clinical Research Clinical Trials Consensus Defect Degenerative Disorder Development Diabetic Neuropathies Dipeptides Disease Disease Progression Drug Exposure Drug Kinetics Engineering Enzymes Etiology Evaluation FDA approved Future GIPR gene GLP-2 GLP-I receptor Gastric Inhibitory Polypeptide Glucagon Glucagon Receptor Glutamates Goals Head Hormones Idiopathic Parkinson Disease Improve Access In Vitro Injury Investigation Knowledge Laboratories Lead Legal patent Libraries Ligands Link Manufactured football Mediating Military Personnel Modification Molecular Morbidity - disease rate Motor Neuron Disease N-terminal Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Parkinson Disease Patients Peptide Hydrolases Peptide Library Peptides Pharmaceutical Preparations Pharmacodynamics Phase Prevention Property Public Health Publishing Receptor Activation Resistance Risk Rodent Model Side Site Soccer Sports Stream TBI treatment Therapeutic Traumatic Brain Injury Vascular Dementia age related age related neurodegeneration analog attenuation base behavioral study blood-brain barrier penetration chemical stability contact sports cost design effective therapy excitotoxicity exenatide gastric inhibitory polypeptide receptor glucagon-like peptide 1 glucose metabolism improved in vivo lead candidate liraglutide loss of function mild traumatic brain injury motor function improvement mouse model neuroinflammation neuron loss neuroprotection novel strategies peptide analog peptide drug peptide hormone analog pharmacokinetics and pharmacodynamics phase 2 study physical insult pre-clinical public health relevance receptor safety assessment screening therapeutic candidate therapeutic effectiveness translational pipeline

项目摘要

Project Summary Morbidity associated with neuronal degeneration and dysfunction poses an increasing public health burden. Among the wide range of etiologies that result in neuronal dysfunction, including chronic conditions such as Alzheimer’s and Parkinson’s disease and vascular dementias, one major cause that has been largely unnoticed but is increasingly recognized as a major concern is traumatic brain injury (TBI). Even mild TBI (mTBI), which is highly prevalent and underestimated in sport related injuries especially in American football and soccer and in the military, can have persistent, and sometimes progressive, long-term debilitating effects. There is now evidence that even a single traumatic brain injury, beyond causing reversible short-term defects, can precipitate or accelerate age-related other neurodegenerative disease entities as noted above. The unmet need is to develop a neuroprotective or disease-modifying therapy that can slow or halt disease progression. Recently, a synthetic monomeric peptide compound that acts as an agonist for three separate receptors (“triagonist”), GLP-1R (glucagon-like peptide-1 receptor), GIPR (glucose-dependent insulinotropic polypeptide receptor) and the glucagon receptor that control and direct glucose metabolism, seems to have beneficial neurotrophic and neuroprotective effects useful for conferring neuroprotection and mitigating the behavioral deficits in animal models of TBI and Alzheimer’s disease. We have invented chemical modifications at the N-terminal end of this triagonist peptide that confer high chemical stability while conserving native potency and efficacy. Furtheremore, these and other peptide modifications that rely on side chain attachments open the door for the design of further improved peptide hormone analogs that are specifically designed to facilitate access to the brain and protect neuronal cells. Such compounds will provide candidate therapeutics that can move into the translational pipeline, to be pursued in subsequent phase II studies that will initially focus on developing a treatment for mTBI. We will synthesize a library of peptides and select for high potency target receptor activation and maximized access to the brain. Moving further through the screening funnel, candidates will be further prioritized based on their ability to rescue neuronal cells from oxidative stress and glutamate excitotoxicity–induced cell death, and based on drug-induced attenuation of microglial neuroinflammation. The deliverable in phase I will be the identification of a lead candidate and a backup compound. These molecules will provide the basis for future phase II studies to further determine PK/PD, and to explore therapeutic effectiveness in behavioral studies with mouse models of mTBI as a prelude to preclinical (and clinical) studies.

项目总结