PROJECT SUMMARY Emerging peptide-, protein-, and nucleic acid-based therapeutics for the treatment of Alzheimer’s disease and other neurologic conditions are blocked from diffusing into the brain by the blood–brain barrier (BBB). The long-term goal of this project is to deliver large therapeutic cargo such as these into the brain using designed BBB-crossing drug-delivery vehicles. The overall objectives are to (i) leverage recent breakthroughs in computational peptide design to yield new knowledge about BBB permeability and (ii) to designed from scratch new proteins that ferry cargo into the brain by exploiting natural systems that the brain uses to receive nutrients and signals. The central hypothesis is that the systematic design of functional biomolecules will yield new insights and tools for improving the delivery of large biomolecule therapeutics into the brain. The specific aims are: 1) to systematically and rationally discover the physiochemical properties which confer BBB permeability to designed peptide macrocycles (a promising new class of therapeutics); 2) to computationally design small, hyperstable proteins which bind to receptors that naturally cycle between the blood- and brain-side of the BBB; and 3) to fuse the binding proteins generated in Aim 2 to various drug-binding/packaging proteins, thereby creating protein assemblies that ferry large therapeutics into the brain. This project is innovative because it proposes to resolve a long-standing barrier to the treatment of neurologic diseases (namely, the difficulty of delivering therapeutics into the brain) by designing from scratch new BBB-crossing drug delivery vehicles. The project is significant because it is expected to provide tools which will improve outcomes in a range of future clinical trials of therapeutics which require delivery into the brain.