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.