{"doi":"10.1101/2022.08.22.504611","title":"Genetically-Encoded Discovery of Perfluoroaryl-Macrocycles that Bind to Albumin and Exhibit Extended Circulation <i>in-vivo</i>","abstract":"Abstract In this paper, we report selection of albumin-binding macrocyclic peptides from genetically encoded libraries of peptides modified by perfluoroaryl-cysteine S N Ar chemistry. Modification of phage-displayed libraries SXCX n C-phage, n =3–5, where X is any amino acid except for cysteine by decafluoro-diphenylsulfone ( DFS ), yields genetically-encoded library of octafluoro-diphen-ylsulfone-crosslinked macrocycles ( OFS -SXCX n C-phage). Selection from these libraries using albumin as a bait identified a family of significantly enriched perfluoroaryl-macrocycles. Synthesis of perfluoroaryl-macrocycles predicted by phage display and testing their binding properties by 19 F NMR and fluorescent polarization identified OFS -macrocycle with SICRFFC sequence as the most potent albumin binder. We observed that OFS -macrocycles slowly react with biological nucleophiles such as glutathione. Replacing decafluoro-diphenylsulfone by nearly isosteric pentafluorophenyl sulfide yielded perfluorophenylsulfide ( PFS )-crosslinked macrocycles devoid of undesired reactivity. The augmented lead PFS -macrocycle with SICRFFC sequence exhibited K D = 4–6 μM towards human serum albumin and similar affinities towards rat and mouse albumins. When injected in mouse, the PFS -SICRFFCGGG compound was significantly retained in circulation in vivo when compared to control PFS -macrocyclic peptide. The perfluoroaryl-macrocycles with SICRFFC motif are the smallest known peptide macrocycle with significant affinity for human albumin and they are a productive starting point for future development of compact macrocycles with predictable circulation half-life in vivo .","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":310798,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9617,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":118138,"name":"Steven E. Kirberger","orcid":null,"position":1,"is_corresponding":false},{"id":1006796,"name":"Ryan Qiu","orcid":"0000-0002-7586-8475","position":2,"is_corresponding":false},{"id":1006797,"name":"Arunika I. Ekanayake","orcid":"0000-0002-2539-446X","position":3,"is_corresponding":false},{"id":648458,"name":"Payam Kelich","orcid":"0000-0002-6441-6326","position":4,"is_corresponding":false},{"id":893468,"name":"Susmita Sarkar","orcid":null,"position":5,"is_corresponding":false},{"id":1007141,"name":"Edgar R. Alvizo-Paez","orcid":null,"position":6,"is_corresponding":false},{"id":813944,"name":"Jiayuan Miao","orcid":null,"position":7,"is_corresponding":false},{"id":1006798,"name":"Shiva Kalhor‐Monfared","orcid":"0000-0002-8882-7373","position":8,"is_corresponding":false},{"id":679334,"name":"John J. Dwyer","orcid":null,"position":9,"is_corresponding":false},{"id":1006799,"name":"John M. Nuss","orcid":"0000-0003-1213-3233","position":10,"is_corresponding":false},{"id":651034,"name":"Yu‐Shan Lin","orcid":"0000-0001-6460-2877","position":11,"is_corresponding":false},{"id":296111,"name":"Matthew S. Macauley","orcid":"0000-0003-4579-1048","position":12,"is_corresponding":false},{"id":648462,"name":"Lela Vuković","orcid":"0000-0002-9053-5708","position":13,"is_corresponding":false},{"id":118141,"name":"William C. K. Pomerantz","orcid":"0000-0002-0163-4078","position":14,"is_corresponding":false},{"id":678345,"name":"Ratmir Derda","orcid":"0000-0003-1365-6570","position":15,"is_corresponding":false},{"id":678341,"name":"Jeffrey Y. K. Wong","orcid":"0000-0003-2720-7872","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:33:24.451129Z","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":[]}