2020/04/15 by Zachary R. Crook, Emily J. Girard, Gregory P. Sevilla +14 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Amino Acid Enzymes and Metabolism #Drug Transport and Resistance Mechanisms #Cholesterol and Lipid Metabolism
paper · pdf · doi:10.1016/j.jmb.2020.04.002
openalex publication_date 2020/04/15 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
The impenetrability of the blood–brain barrier (BBB) to most conventional drugs impedes the treatment of central nervous system (CNS) disorders. Interventions for diseases like brain cancer, neurodegeneration, or age-associated inflammatory processes require varied approaches to CNS drug delivery. Cystine-dense peptides (CDPs) have drawn recent interest as drugs or drug-delivery vehicles. Found throughout the phylogenetic tree, often in drug-like roles, their size, stability, and protein interaction capabilities make CDPs an attractive mid-size biologic scaffold to complement conventional antibody-based drugs. Here, we describe the identification, maturation, characterization, and utilization of a CDP that binds to the transferrin receptor (TfR), a native receptor and BBB transporter for the iron chaperone transferrin. We developed variants with varying binding affinities (KD as low as 216 pM), co-crystallized it with the receptor, and confirmed murine cross-reactivity. It accumulates in the mouse CNS at ~ 25% of blood levels (CNS blood content is only ~ 1%–6%) and delivers neurotensin, an otherwise non-BBB-penetrant neuropeptide, at levels capable of modulating CREB signaling in the mouse brain. Our work highlights the utility of CDPs as a diverse, easy-to-screen scaffold family worthy of inclusion in modern drug discovery strategies, demonstrated by the discovery of a candidate CNS drug delivery vehicle ready for further optimization and preclinical development.