{"doi":"10.1021/acsabm.0c01229","title":"Regulation of Lipoprotein Homeostasis by Self-Assembling Peptides","abstract":"High levels of serum low-density lipoprotein (LDL) cholesterol contribute to atherosclerosis, a key risk factor of cardiovascular diseases. PCSK9 is a circulatory enzyme that downregulates expression of hepatic LDL receptors, concomitantly increasing serum LDL-C. This work investigates a small, self-assembling peptide, EPep2-8, as a peptide inhibitor of PCSK9. EPep2-8 is a multidomain peptide comprising a self-assembling domain, E2, conjugated to a bioactive domain, Pep2-8, previously shown to inhibit PCSK9. The E2 domain facilitates self-assembly of EPep2-8 into long, nanofibrous polymers with an underlying supramolecular β-sheet secondary structure. Intermolecular interactions between nanofibers drive EPep2-8 to form a thixotropic and cytocompatible hydrogel in aqueous and charge-neutral solutions. These properties enable EPep2-8 to be delivered as an in situ depot for regulation of lipoprotein homeostasis. In surface plasmon resonance studies, EPep2-8 bound specifically to PCSK9 with an apparent, noncovalent, and irreversible dissociation, significantly improving the binding affinity of Pep2-8 alone (KD = 667 ± 48 nM). Increased binding affinity of EPep2-8 is primarily due to the superstoichiometric interaction of the peptide with PCSK9. Promisingly, EPep2-8 retains bioactivity in vitro, engendering dose-dependent uptake of LDL-C in hepatocytes. This mechanism of self-assembly on a target site may be a simple method to improve the affinity of peptide inhibitors.","journal":"ACS Applied Bio Materials","year":2020,"id":81580,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9651,"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":423030,"name":"Candice Casillas","orcid":null,"position":1,"is_corresponding":false},{"id":315577,"name":"Zain Siddiqui","orcid":"0000-0001-9201-3084","position":2,"is_corresponding":false},{"id":421897,"name":"Biplab Sarkar","orcid":"0000-0002-9298-2392","position":3,"is_corresponding":false},{"id":423031,"name":"Sreya Sanyal","orcid":null,"position":4,"is_corresponding":false},{"id":421898,"name":"Peter K. Nguyen","orcid":"0000-0001-9867-887X","position":5,"is_corresponding":false},{"id":423032,"name":"Ka Kyung Kim","orcid":null,"position":6,"is_corresponding":false},{"id":421899,"name":"Abhishek Roy","orcid":"0000-0001-6737-3571","position":7,"is_corresponding":false},{"id":316308,"name":"Patricia Iglesias-Montoro","orcid":null,"position":8,"is_corresponding":false},{"id":423033,"name":"Saloni Patel","orcid":null,"position":9,"is_corresponding":false},{"id":423034,"name":"Frank Podlaski","orcid":null,"position":10,"is_corresponding":false},{"id":423035,"name":"Peter Tolias","orcid":null,"position":11,"is_corresponding":false},{"id":421900,"name":"William T. Windsor","orcid":"0000-0002-9903-1127","position":12,"is_corresponding":false},{"id":315580,"name":"Vivek Kumar","orcid":"0000-0001-7536-9281","position":13,"is_corresponding":false},{"id":423029,"name":"Victoria Harbour","orcid":null,"position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-18T21:52:58.921847Z","pmid":"35019574","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":[]}