Rapid C–S<sup>+</sup> Bond Cleavage via 1,6-Benzyl Elimination for Traceless Modification of Bioactive Peptides
Peptides and proteins are invaluable therapeutics and biological tools, where stimuli-responsive and fully reversible conjugation chemistry is essential to advances in drug delivery systems and chemical biology. However, methods that allow precise conjugation, efficient regulation of biochemical fun...
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2025
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| _version_ | 1852019661805191168 |
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| author | Yu Chai (4014536) |
| author2 | Can Yu (6517646) Zhi Chen (222749) Wenbin Duan (21485167) Huanwen Chen (1461205) Xunxiang Qiu (21485170) Zhengyang Xu (11447647) Shengzhang Liu (16459613) Anastasia Danilenko (21485173) Gilles Frison (1278360) Valérie Alezra (1849048) Emeric Miclet (1896709) Xiang Li (114679) Yang Wan (323627) |
| author2_role | author author author author author author author author author author author author author |
| author_facet | Yu Chai (4014536) Can Yu (6517646) Zhi Chen (222749) Wenbin Duan (21485167) Huanwen Chen (1461205) Xunxiang Qiu (21485170) Zhengyang Xu (11447647) Shengzhang Liu (16459613) Anastasia Danilenko (21485173) Gilles Frison (1278360) Valérie Alezra (1849048) Emeric Miclet (1896709) Xiang Li (114679) Yang Wan (323627) |
| author_role | author |
| dc.creator.none.fl_str_mv | Yu Chai (4014536) Can Yu (6517646) Zhi Chen (222749) Wenbin Duan (21485167) Huanwen Chen (1461205) Xunxiang Qiu (21485170) Zhengyang Xu (11447647) Shengzhang Liu (16459613) Anastasia Danilenko (21485173) Gilles Frison (1278360) Valérie Alezra (1849048) Emeric Miclet (1896709) Xiang Li (114679) Yang Wan (323627) |
| dc.date.none.fl_str_mv | 2025-06-04T17:41:29Z |
| dc.identifier.none.fl_str_mv | 10.1021/jacs.5c04329.s002 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/dataset/Rapid_C_S_sup_sup_Bond_Cleavage_via_1_6-Benzyl_Elimination_for_Traceless_Modification_of_Bioactive_Peptides/29238982 |
| dc.rights.none.fl_str_mv | CC BY-NC 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biophysics Biochemistry Pharmacology Inorganic Chemistry Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified weakly acidic conditions sup >+</ sup enhanced enzymatic stability drug delivery systems allow precise conjugation stable c – selectively alkylating met reversibly stapled peptides rapid c – bioactive peptides peptides terminal met met ), containing peptides antimicrobial peptides work describes versatile chemistry traceless modification therapeutic effects switchable conformations reduced toxicity peptide community pegylated prodrugs invaluable therapeutics greatly benefit first time extracellular sites efficient regulation diverse applications customized recovery chemical biology caged neuropeptides bioorthogonal control biological tools biochemical functions benzyl elimination |
| dc.title.none.fl_str_mv | Rapid C–S<sup>+</sup> Bond Cleavage via 1,6-Benzyl Elimination for Traceless Modification of Bioactive Peptides |
| dc.type.none.fl_str_mv | Dataset info:eu-repo/semantics/publishedVersion dataset |
| description | Peptides and proteins are invaluable therapeutics and biological tools, where stimuli-responsive and fully reversible conjugation chemistry is essential to advances in drug delivery systems and chemical biology. However, methods that allow precise conjugation, efficient regulation of biochemical functions, and customized recovery of parent peptides remain underdeveloped. Here, we introduce a straightforward yet powerful reversible chemical strategy targeting methionine (Met), a widespread yet low abundance amino acid in peptides and proteins. By selectively alkylating Met-containing peptides under weakly acidic conditions, we form a stable C–S<sup>+</sup> bond, which can be cleaved rapidly via 1,6-benzyl elimination upon stimulus. This versatile chemistry is demonstrated in diverse applications: (i) PEGylated prodrugs of antimicrobial peptides with reduced toxicity and enhanced enzymatic stability, (ii) esterase-responsive peptide–peptide inhibitor conjugates (PPICs) with improved cell membrane permeability and therapeutic effects, (iii) reversibly stapled peptides with switchable conformations for targeting both intra- and extracellular sites, and (iv) bioorthogonal control of C-terminal Met-caged neuropeptides. Overall, this work describes, for the first time, a valuable traceless modification strategy that promises to greatly benefit the peptide community and advance the field of chemical biology. |
| eu_rights_str_mv | openAccess |
| id | Manara_b2ff5502bae73e26debfb2eeaf9dbe71 |
| identifier_str_mv | 10.1021/jacs.5c04329.s002 |
| network_acronym_str | Manara |
| network_name_str | ManaraRepo |
| oai_identifier_str | oai:figshare.com:article/29238982 |
| publishDate | 2025 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY-NC 4.0 |
| spelling | Rapid C–S<sup>+</sup> Bond Cleavage via 1,6-Benzyl Elimination for Traceless Modification of Bioactive PeptidesYu Chai (4014536)Can Yu (6517646)Zhi Chen (222749)Wenbin Duan (21485167)Huanwen Chen (1461205)Xunxiang Qiu (21485170)Zhengyang Xu (11447647)Shengzhang Liu (16459613)Anastasia Danilenko (21485173)Gilles Frison (1278360)Valérie Alezra (1849048)Emeric Miclet (1896709)Xiang Li (114679)Yang Wan (323627)BiophysicsBiochemistryPharmacologyInorganic ChemistryBiological Sciences not elsewhere classifiedChemical Sciences not elsewhere classifiedweakly acidic conditionssup >+</ supenhanced enzymatic stabilitydrug delivery systemsallow precise conjugationstable c –selectively alkylating metreversibly stapled peptidesrapid c –bioactive peptides peptidesterminal metmet ),containing peptidesantimicrobial peptideswork describesversatile chemistrytraceless modificationtherapeutic effectsswitchable conformationsreduced toxicitypeptide communitypegylated prodrugsinvaluable therapeuticsgreatly benefitfirst timeextracellular sitesefficient regulationdiverse applicationscustomized recoverychemical biologycaged neuropeptidesbioorthogonal controlbiological toolsbiochemical functionsbenzyl eliminationPeptides and proteins are invaluable therapeutics and biological tools, where stimuli-responsive and fully reversible conjugation chemistry is essential to advances in drug delivery systems and chemical biology. However, methods that allow precise conjugation, efficient regulation of biochemical functions, and customized recovery of parent peptides remain underdeveloped. Here, we introduce a straightforward yet powerful reversible chemical strategy targeting methionine (Met), a widespread yet low abundance amino acid in peptides and proteins. By selectively alkylating Met-containing peptides under weakly acidic conditions, we form a stable C–S<sup>+</sup> bond, which can be cleaved rapidly via 1,6-benzyl elimination upon stimulus. This versatile chemistry is demonstrated in diverse applications: (i) PEGylated prodrugs of antimicrobial peptides with reduced toxicity and enhanced enzymatic stability, (ii) esterase-responsive peptide–peptide inhibitor conjugates (PPICs) with improved cell membrane permeability and therapeutic effects, (iii) reversibly stapled peptides with switchable conformations for targeting both intra- and extracellular sites, and (iv) bioorthogonal control of C-terminal Met-caged neuropeptides. Overall, this work describes, for the first time, a valuable traceless modification strategy that promises to greatly benefit the peptide community and advance the field of chemical biology.2025-06-04T17:41:29ZDatasetinfo:eu-repo/semantics/publishedVersiondataset10.1021/jacs.5c04329.s002https://figshare.com/articles/dataset/Rapid_C_S_sup_sup_Bond_Cleavage_via_1_6-Benzyl_Elimination_for_Traceless_Modification_of_Bioactive_Peptides/29238982CC BY-NC 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/292389822025-06-04T17:41:29Z |
| spellingShingle | Rapid C–S<sup>+</sup> Bond Cleavage via 1,6-Benzyl Elimination for Traceless Modification of Bioactive Peptides Yu Chai (4014536) Biophysics Biochemistry Pharmacology Inorganic Chemistry Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified weakly acidic conditions sup >+</ sup enhanced enzymatic stability drug delivery systems allow precise conjugation stable c – selectively alkylating met reversibly stapled peptides rapid c – bioactive peptides peptides terminal met met ), containing peptides antimicrobial peptides work describes versatile chemistry traceless modification therapeutic effects switchable conformations reduced toxicity peptide community pegylated prodrugs invaluable therapeutics greatly benefit first time extracellular sites efficient regulation diverse applications customized recovery chemical biology caged neuropeptides bioorthogonal control biological tools biochemical functions benzyl elimination |
| status_str | publishedVersion |
| title | Rapid C–S<sup>+</sup> Bond Cleavage via 1,6-Benzyl Elimination for Traceless Modification of Bioactive Peptides |
| title_full | Rapid C–S<sup>+</sup> Bond Cleavage via 1,6-Benzyl Elimination for Traceless Modification of Bioactive Peptides |
| title_fullStr | Rapid C–S<sup>+</sup> Bond Cleavage via 1,6-Benzyl Elimination for Traceless Modification of Bioactive Peptides |
| title_full_unstemmed | Rapid C–S<sup>+</sup> Bond Cleavage via 1,6-Benzyl Elimination for Traceless Modification of Bioactive Peptides |
| title_short | Rapid C–S<sup>+</sup> Bond Cleavage via 1,6-Benzyl Elimination for Traceless Modification of Bioactive Peptides |
| title_sort | Rapid C–S<sup>+</sup> Bond Cleavage via 1,6-Benzyl Elimination for Traceless Modification of Bioactive Peptides |
| topic | Biophysics Biochemistry Pharmacology Inorganic Chemistry Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified weakly acidic conditions sup >+</ sup enhanced enzymatic stability drug delivery systems allow precise conjugation stable c – selectively alkylating met reversibly stapled peptides rapid c – bioactive peptides peptides terminal met met ), containing peptides antimicrobial peptides work describes versatile chemistry traceless modification therapeutic effects switchable conformations reduced toxicity peptide community pegylated prodrugs invaluable therapeutics greatly benefit first time extracellular sites efficient regulation diverse applications customized recovery chemical biology caged neuropeptides bioorthogonal control biological tools biochemical functions benzyl elimination |