{"doi":"10.1016/j.jmb.2020.04.002","title":"A TfR-Binding Cystine-Dense Peptide Promotes Blood–Brain Barrier Penetration of Bioactive Molecules","abstract":"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.","journal":"Journal of Molecular Biology","year":2020,"id":95832,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":475518,"name":"Emily J. Girard","orcid":"0000-0003-1857-0194","position":1,"is_corresponding":false},{"id":475519,"name":"Gregory P. Sevilla","orcid":"0000-0002-6590-9413","position":2,"is_corresponding":false},{"id":476314,"name":"Morgan Merrill","orcid":null,"position":3,"is_corresponding":false},{"id":476315,"name":"Della Friend","orcid":null,"position":4,"is_corresponding":false},{"id":475520,"name":"Peter B. Rupert","orcid":"0000-0003-1011-0302","position":5,"is_corresponding":false},{"id":475521,"name":"Fiona Pakiam","orcid":"0000-0001-6292-1137","position":6,"is_corresponding":false},{"id":475522,"name":"Elizabeth Nguyen","orcid":"0000-0002-7677-5211","position":7,"is_corresponding":false},{"id":475523,"name":"Chunfeng Yin","orcid":"0000-0003-3876-6231","position":8,"is_corresponding":false},{"id":475524,"name":"Raymond Ruff","orcid":"0000-0002-7189-1221","position":9,"is_corresponding":false},{"id":475525,"name":"Gene Hopping","orcid":"0000-0001-8409-1867","position":10,"is_corresponding":false},{"id":475526,"name":"Andrew D. Strand","orcid":"0000-0001-9882-454X","position":11,"is_corresponding":false},{"id":476316,"name":"Kathryn A. K. Finton","orcid":null,"position":12,"is_corresponding":false},{"id":476317,"name":"Margo Coxon","orcid":null,"position":13,"is_corresponding":false},{"id":475527,"name":"Andrew J. Mhyre","orcid":"0000-0002-9206-3150","position":14,"is_corresponding":false},{"id":475528,"name":"Roland K. Strong","orcid":"0000-0002-1338-2189","position":15,"is_corresponding":false},{"id":30180,"name":"James M. Olson","orcid":"0000-0001-5990-6534","position":16,"is_corresponding":false},{"id":475517,"name":"Zachary R. Crook","orcid":"0000-0002-1142-9748","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-18T22:33:57.534608Z","pmid":"32304700","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}