{"doi":"10.1016/j.jbc.2025.110594","title":"Mechanism of inhibition of acid-mediated transthyretin aggregation by designed peptides","abstract":"Aggregation of transthyretin (TTR) causes TTR cardiomyopathy and polyneuropathy through amyloidosis. To initialize TTR aggregation, the native TTR tetramer first dissociates to a monomeric intermediate, which misfolds and self-assembles to oligomers, eventually forming insoluble aggregates and fibrils. Peptide inhibitors have been designed to cap two β-strands that are buried in the well-folded tetramer but are solvent-exposed in the monomeric aggregation intermediate. However, how these peptides affect the reaction kinetics of individual steps in the multi-step TTR aggregation pathway remains unknown. Here, we integrated 19 F-NMR and kinetic modeling to determine aggregation reaction rates of individual steps with the peptide inhibitors and extract the free energy landscape along the TTR aggregation pathway. We found direct kinetic evidence that the peptide inhibitors bind to monomeric intermediates and misfolded tetramers at acidic pH, but do not bind to structured TTR monomers or tetramers at neutral pH. In addition, the peptides do not bind to amorphous aggregates formed at acidic pH and physiological temperature in vitro , in contrast to the previously reported findings that these peptides recognize ex vivo TTR fibrils derived from patients with TTR amyloidosis. Interestingly, the peptides bind to soluble oligomers formed at acidic pH and low temperature in vitro , suggesting that these oligomers may share structural similarity with misfolded monomeric intermediates and patient-derived TTR fibrils. Our methods provide quantitative and mechanistic details for peptide-inhibited TTR aggregation.","journal":"Journal of Biological Chemistry","year":2025,"id":546056,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":985851,"name":"Rose Pedretti","orcid":"0000-0001-6354-3588","position":1,"is_corresponding":false},{"id":493462,"name":"H. Jane Dyson","orcid":"0000-0001-6855-3398","position":2,"is_corresponding":false},{"id":640664,"name":"Lorena Saelices","orcid":"0000-0002-1904-2150","position":3,"is_corresponding":false},{"id":449081,"name":"Peter E. Wright","orcid":"0000-0002-1368-0223","position":4,"is_corresponding":false},{"id":919706,"name":"Xun Sun","orcid":"0000-0002-8079-5530","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-19T02:53:27.751050Z","pmid":"40816471","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":[]}