{"doi":"10.1101/2020.09.09.290379","title":"Unprotected Peptide Macrocyclization and Stapling via A Fluorine-Thiol Displacement Reaction","abstract":"Abstract Stapled peptides serve as a powerful tool for probing protein-protein interactions, but its application has been largely impeded by the limited cellular uptake. Here we report the discovery of a facile peptide macrocyclization and stapling strategy based on a fluorine thiol displacement reaction (FTDR), which renders a class of peptide analogues with enhanced stability, affinity, and cell permeability. This new approach enabled selective modification of the orthogonal fluoroacetamide side chains in unprotected peptides, with the identified 1,3-benzenedimethanethiol linker promoting alpha helicity of a variety of peptide substrates, as corroborated by molecular dynamics simulations. The cellular uptake of these stapled peptides was universally enhanced compared to the classic ring-closing metathesis (RCM) stapled peptides. Pilot mechanism studies suggested that the uptake of FTDR-stapled peptides may involve multiple endocytosis pathways. Consistent with the improved cell permeability, the FTDR-stapled lead Axin analogues demonstrated better inhibition of cancer cell growth than the RCM-stapled analogues. Graphical Abstract","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127332,"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":0.9517,"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":402255,"name":"Samuel L. Junod","orcid":"0000-0002-4288-0240","position":1,"is_corresponding":false},{"id":576026,"name":"Si Zhang","orcid":"0000-0002-1164-2020","position":2,"is_corresponding":false},{"id":526349,"name":"Zakey Yusuf Buuh","orcid":null,"position":3,"is_corresponding":false},{"id":576027,"name":"Yifu Guan","orcid":"0000-0002-0800-7069","position":4,"is_corresponding":false},{"id":576635,"name":"Kishan H. Kaneria","orcid":null,"position":5,"is_corresponding":false},{"id":576028,"name":"Zhigang Lyu","orcid":"0000-0002-6903-3965","position":6,"is_corresponding":false},{"id":328251,"name":"Vincent A. Voelz","orcid":"0000-0002-1054-2124","position":7,"is_corresponding":false},{"id":402258,"name":"Weidong Yang","orcid":"0000-0002-3649-1863","position":8,"is_corresponding":false},{"id":525465,"name":"Rongsheng E. Wang","orcid":"0000-0002-5749-7447","position":9,"is_corresponding":false},{"id":576025,"name":"Md Shafiqul Islam","orcid":"0000-0001-9617-3376","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-18T23:15:30.930746Z","pmid":null,"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":[]}