An under-explored therapeutic approach to treating progressive dementia is to combat neurodegeneration with growth factor therapy to promote nerve regeneration and re-establish brain homeostasis. The overall objective of this R01 supplement is to leverage our current efforts to develop computational and wet lab methods for the de novo design of cytokine mimetics for immune oncology applications and apply these methods to the development of a blood brain barrier (BBB) penetrant “painless” nerve growth factor (NGF) mimetic. NGF is a neurotrophic protein that promotes nerve growth and also plays a critical role in pain signaling. By signalling through the cell receptors p75NTR and TrkA (a receptor tyrosine kinase), it serves to establish and maintain nerve homeostasis in the peripheral and central nervous system. However, prior attempts to promote neuro-regeneration and attenuate progressive neurodegeneration in Alzheimer’s disease (AD) have suffered from two issues. First, neurotrophic growth factor proteins do not easily cross the BBB and must be delivered invasively by intracranial injection or by spinal cord installation. Second, as observed for NGF, side effects of chronic pain and migraine ultimately halted NGF clinical trials. The recent discovery of a naturally occurring “painless” NGF variant that signals only through TrkA inspires our proposal to design a blood brain barrier (BBB) penetrant mimetic of “painless” NGF. The long term goal is to address both issues by developing a drug candidate that can be self-administered by subcutaneous injection to promote neuronal re-growth and homeostasis, having therapeutic relevance for treatment of both cancer-related cognitive impairment (CRCI) and AD, by slowing, stopping or reversing the neurodegeneration associated with cognitive impairment in these disorders. This supplement request directly address the following research areas in NCI’s award portfolio that are relevant to NOT-AG-21-018, including: (i) cancer treatment-related neurocognitive function; (ii) treatment tolerability, toxicity, and symptom management; (iii) attention, sensation, and perception; and (iv) cancer caregiving. The specific aims are to (A) Computationally design symmetric homo-dimeric TrkA specific minibinder agonists. (B) Characterize TrkA minibinder agonists in TrkA signaling cell assays. (C) Design transferrin receptor (TtfR) minibinder fusions to TrkA minibinder agonists for BBB traversal. (D) Characterize TrfR minibinder - TrkA minibinder agonists in transgenic mice with the human transferrin receptor (hTrfR). This research proposal is innovative because it utilizes de novo protein design to create stable minibinder proteins, from first principles, that have TrkA target specificity, ease of manufacturing, and stability features that overcome the shortcomings of the natural parent “painless” NGF which is not sufficiently stable to be a drug candidate. Our de novo protein design approach results in therapeutic agents ...