{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T14:36:10Z","timestamp":1787150170172,"version":"build-2736575974"},"reference-count":32,"publisher":"American Chemical Society (ACS)","issue":"32","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100018928","name":"Westlake University","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100018928","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100022963","name":"Key Research and Development Program of Zhejiang Province","doi-asserted-by":"publisher","award":["2024SDXHDX0002"],"award-info":[{"award-number":["2024SDXHDX0002"]}],"id":[{"id":"10.13039\/100022963","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100022963","name":"Key Research and Development Program of Zhejiang Province","doi-asserted-by":"publisher","award":["2025XDHSDX0002"],"award-info":[{"award-number":["2025XDHSDX0002"]}],"id":[{"id":"10.13039\/100022963","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100032572","name":"Westlake Education Foundation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100032572","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"National Basic Research Program of China","doi-asserted-by":"publisher","award":["2024YFC3407400"],"award-info":[{"award-number":["2024YFC3407400"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32120103013"],"award-info":[{"award-number":["32120103013"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["323B2039"],"award-info":[{"award-number":["323B2039"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["T2596081"],"award-info":[{"award-number":["T2596081"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Few advances have effectively addressed the challenge of selectively activating aspartic acid (Asp) side chains. The \u03b2-carboxyl group of Asp remains underutilized as a reactive handle due to its limited reactivity under biocompatible conditions, its susceptibility to competing aspartimide formation, and the difficulty of achieving site-selectivity among chemically indistinguishable carboxyl groups on glutamic acid (Glu) side chains and the C-terminus. Here, we report a copper\/organoboron synergistic system that enables direct and selective activation of the Asp side chain within Asp-His motifs, forming Lys-Asp isopeptide bonds under neutral aqueous conditions and exhibiting broad compatibility with unprotected peptides containing all canonical amino acids, including Glu and Asp residues outside the recognition motif. The method is applied to the synthesis of cyclic peptides (14- to 38-membered rings), bicyclic architectures, and diverse bioactive sequences, including the RGD peptide. The utility of this Asp activation strategy extends to protein engineering, as demonstrated by the head-to-tail cyclization of the de novo-designed protein ABLE and protein\u2013protein ligation mediated by a heterodimeric coiled-coil. Beyond cyclization, we identified a -DAGGDHLP- tag that exploits the activated Asp residue for site-specific peptide conjugation with small-molecule amines. This dual-reagent activation strategy provides an enzyme-free solution for Asp side-chain chemistry, expanding the synthetic toolkit for peptide and protein engineering.<\/jats:p>","DOI":"10.1021\/jacs.6c09712","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T21:02:23Z","timestamp":1785963743000},"page":"34687-34695","source":"Crossref","is-referenced-by-count":0,"title":["Synergistic Copper-Organoboron\nActivation of Aspartic\nAcid Enabled Peptide Cyclization and Conjugation"],"prefix":"10.1021","volume":"148","author":[{"given":"Yingjie","family":"Lei","sequence":"first","affiliation":[{"name":"Westlake University , , , ,","place":["Hangzhou, Zhejiang, China, 310030"]},{"name":"Westlake Laboratory of Life Sciences and Biomedicine , , ,","place":["Hangzhou, Zhejiang, China, 310024"]},{"name":"Westlake Institute for Advanced Study , , , ,","place":["Hangzhou, Zhejiang, China, 310024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9649-9536","authenticated-orcid":true,"given":"Kai","family":"Zhao","sequence":"additional","affiliation":[{"name":"Westlake University , , , ,","place":["Hangzhou, Zhejiang, China, 310030"]},{"name":"Westlake Laboratory of Life Sciences and Biomedicine , , ,","place":["Hangzhou, Zhejiang, China, 310024"]},{"name":"Westlake Institute for Advanced Study , , , ,","place":["Hangzhou, Zhejiang, China, 310024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengzhun","family":"Guo","sequence":"additional","affiliation":[{"name":"Westlake University , , , ,","place":["Hangzhou, Zhejiang, China, 310030"]},{"name":"Westlake Laboratory of Life Sciences and Biomedicine , , ,","place":["Hangzhou, Zhejiang, China, 310024"]},{"name":"Westlake Institute for Advanced Study , , , ,","place":["Hangzhou, Zhejiang, China, 310024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo Alexander","family":"Weis","sequence":"additional","affiliation":[{"name":"Westlake University , , , ,","place":["Hangzhou, Zhejiang, China, 310030"]},{"name":"Westlake Laboratory of Life Sciences and Biomedicine , , ,","place":["Hangzhou, Zhejiang, China, 310024"]},{"name":"Westlake Institute for Advanced Study , , , ,","place":["Hangzhou, Zhejiang, China, 310024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Fang","sequence":"additional","affiliation":[{"name":"Westlake University , , , ,","place":["Hangzhou, Zhejiang, China, 310030"]},{"name":"Westlake Laboratory of Life Sciences and Biomedicine , , ,","place":["Hangzhou, Zhejiang, China, 310024"]},{"name":"Westlake Institute for Advanced Study , , , ,","place":["Hangzhou, Zhejiang, China, 310024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yitong","family":"Hu","sequence":"additional","affiliation":[{"name":"Zhejiang University , , , ,","place":["Hangzhou, Zhejiang, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Chen","sequence":"additional","affiliation":[{"name":"Westlake University , , , ,","place":["Hangzhou, Zhejiang, China, 310030"]},{"name":"Westlake Laboratory of Life Sciences and Biomedicine , , ,","place":["Hangzhou, Zhejiang, China, 310024"]},{"name":"Westlake Institute for Advanced Study , , , ,","place":["Hangzhou, Zhejiang, China, 310024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuejiao","family":"Gu","sequence":"additional","affiliation":[{"name":"Westlake University , , , ,","place":["Hangzhou, Zhejiang, China, 310030"]},{"name":"Westlake Laboratory of Life Sciences and Biomedicine , , ,","place":["Hangzhou, Zhejiang, China, 310024"]},{"name":"Westlake Institute for Advanced Study , , , ,","place":["Hangzhou, Zhejiang, China, 310024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Liu","sequence":"additional","affiliation":[{"name":"Zhejiang University , , , ,","place":["Hangzhou, Zhejiang, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6739-2932","authenticated-orcid":true,"given":"Bing","family":"Yang","sequence":"additional","affiliation":[{"name":"Zhejiang University , , , ,","place":["Hangzhou, Zhejiang, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1962-8677","authenticated-orcid":true,"given":"Bobo","family":"Dang","sequence":"additional","affiliation":[{"name":"Westlake University , , , ,","place":["Hangzhou, Zhejiang, China, 310030"]},{"name":"Westlake Laboratory of Life Sciences and Biomedicine , , ,","place":["Hangzhou, Zhejiang, China, 310024"]},{"name":"Westlake Institute for Advanced Study , , , ,","place":["Hangzhou, Zhejiang, China, 310024"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"issue":"30","key":"2026081910214618700_cit1","doi-asserted-by":"publisher","first-page":"3863","DOI":"10.1021\/acs.biochem.7b00536","article-title":"Residue-Specific Peptide Modification:\nA Chemist\u2019s Guide","volume":"56","author":"DeGruyter","year":"2017","journal-title":"Biochemistry"},{"issue":"3","key":"2026081910214618700_cit2","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/s41570-019-0079-1","article-title":"Contemporary\napproaches to site-selective protein modification","volume":"3","author":"Hoyt","year":"2019","journal-title":"Nat. Rev. Chem."},{"issue":"45","key":"2026081910214618700_cit3","doi-asserted-by":"publisher","first-page":"8595","DOI":"10.1016\/j.tet.2011.08.046","article-title":"Aspartimide formation in peptide\nchemistry: occurrence, prevention strategies and the role of N-hydroxylamines","volume":"67","author":"Subiro\u0301s-Funosas","year":"2011","journal-title":"Tetrahedron"},{"issue":"10","key":"2026081910214618700_cit4","doi-asserted-by":"publisher","first-page":"6586","DOI":"10.1021\/acsomega.7b01143","article-title":"FeCl3-Mediated Side\nChain Modification of Aspartic\nAcid- and Glutamic Acid-Containing Peptides on a Solid Support","volume":"2","author":"Giri","year":"2017","journal-title":"ACS Omega"},{"issue":"12","key":"2026081910214618700_cit5","doi-asserted-by":"publisher","first-page":"6615","DOI":"10.1021\/jacs.2c11325","article-title":"Modular Diazo Compound\nfor the Bioreversible Late-Stage Modification of Proteins","volume":"145","author":"Jun","year":"2023","journal-title":"J. Am. Chem. Soc."},{"issue":"4","key":"2026081910214618700_cit6","doi-asserted-by":"publisher","first-page":"2069","DOI":"10.1021\/acs.joc.2c01695","article-title":"Emergent Organoboron\nAcid Catalysts","volume":"89","author":"Graham","year":"2024","journal-title":"J. Org. Chem."},{"issue":"10","key":"2026081910214618700_cit7","doi-asserted-by":"publisher","first-page":"6793","DOI":"10.1021\/acs.chemrev.2c00892","article-title":"Catalytic Approaches to Chemo- and Site-Selective Transformation\nof Carbohydrates","volume":"123","author":"Yamatsugu","year":"2023","journal-title":"Chem. Rev."},{"issue":"80","key":"2026081910214618700_cit8","doi-asserted-by":"publisher","first-page":"11202","DOI":"10.1039\/D4CC02994A","article-title":"Organoboron catalysis for direct\namide\/peptide bond formation","volume":"60","author":"Koshizuka","year":"2024","journal-title":"Chem. Commun."},{"issue":"9","key":"2026081910214618700_cit9","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1701028","article-title":"Borate esters: Simple catalysts for\nthe sustainable synthesis of complex amides","volume":"3","author":"Sabatini","year":"2017","journal-title":"Sci. Adv."},{"issue":"3","key":"2026081910214618700_cit10","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1038\/s41557-022-01110-z","article-title":"A synergistic\nRh(I)\/organoboron-catalysed site-selective carbohydrate functionalization\nthat involves multiple stereocontrol","volume":"15","author":"Rao","year":"2023","journal-title":"Nat. Chem."},{"issue":"3","key":"2026081910214618700_cit11","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202308251","article-title":"Cyclic Peptides for Drug Development","volume":"63","author":"Ji","year":"2024","journal-title":"Angew. Chem., Int. Ed."},{"issue":"1","key":"2026081910214618700_cit12","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1039\/C4CS00246F","article-title":"Peptide stapling\ntechniques based on different macrocyclisation chemistries","volume":"44","author":"Lau","year":"2015","journal-title":"Chem. Soc. Rev."},{"issue":"24","key":"2026081910214618700_cit13","doi-asserted-by":"publisher","first-page":"11725","DOI":"10.1039\/D3CS01066J","article-title":"Recent\nadvances in peptide macrocyclization strategies","volume":"53","author":"Fang","year":"2024","journal-title":"Chem. Soc. Rev."},{"issue":"1","key":"2026081910214618700_cit14","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1038\/s41557-025-01979-6","article-title":"Non-ribosomal peptide\ncyclase-directed chemoenzymatic synthesis of lariat lipopeptides","volume":"18","author":"Kobayashi","year":"2026","journal-title":"Nat. Chem."},{"issue":"2","key":"2026081910214618700_cit15","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1016\/j.chempr.2023.12.003","article-title":"Chemically revertible molecular clasps:\nHydroxamic acid-mediated\npeptide macrocyclization and linearization","volume":"10","author":"Fowler","year":"2024","journal-title":"Chem"},{"issue":"22","key":"2026081910214618700_cit16","doi-asserted-by":"publisher","first-page":"10080","DOI":"10.1021\/jacs.2c04620","article-title":"Construction\nof Complex Macromulticyclic Peptides via Stitching with Formaldehyde\nand Guanidine","volume":"144","author":"Li","year":"2022","journal-title":"J. Am. Chem. Soc."},{"issue":"8","key":"2026081910214618700_cit17","doi-asserted-by":"publisher","first-page":"3644","DOI":"10.1021\/jacs.1c12822","article-title":"A Strategy to Select\nMacrocyclic Peptides Featuring Asymmetric Molecular Scaffolds as Cyclization\nUnits by Phage Display","volume":"144","author":"Oppewal","year":"2022","journal-title":"J. Am. Chem. Soc."},{"issue":"12","key":"2026081910214618700_cit18","doi-asserted-by":"publisher","first-page":"4741","DOI":"10.1021\/jacs.1c00466","article-title":"One-Pot In Vitro Ribosomal\nSynthesis of Macrocyclic Depsipeptides","volume":"143","author":"Nagano","year":"2021","journal-title":"J. Am.\nChem. Soc."},{"issue":"12","key":"2026081910214618700_cit19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1115485109","article-title":"Peptide tag forming a rapid covalent\nbond to a protein, through engineering a bacterial adhesin","volume":"109","author":"Zakeri","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081910214618700_cit20","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202514412","article-title":"Discovery of a Serine-Directed Chemical Reaction for Site-Specific\nProtein Modification via Phage Display Screening","volume":"64","author":"Lei","year":"2025","journal-title":"Angew. Chem., Int. Ed."},{"issue":"1","key":"2026081910214618700_cit21","doi-asserted-by":"publisher","first-page":"123","DOI":"10.3390\/molecules22010123","article-title":"Novel Antihypertensive\nDerived from\nAdlay (Coix larchryma-jobi L. var. ma-yuen Stapf) Glutelin","volume":"22","author":"Li","year":"2017","journal-title":"Molecules"},{"key":"2026081910214618700_cit22","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41538-018-0015-7","article-title":"Purification and characterization\nof antioxidant peptides from cooked\neggs using a dynamic in vitro gastrointestinal model in vascular smooth\nmuscle A7r5 cells","volume":"2","author":"Wang","year":"2018","journal-title":"Npj Sci. Food"},{"key":"2026081910214618700_cit23","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1016\/j.foodchem.2017.10.033","article-title":"Identification\nof novel dipeptidyl peptidase IV (DPP-IV) inhibitory peptides in camel\nmilk protein hydrolysates","volume":"244","author":"Nongonierma","year":"2018","journal-title":"Food Chem."},{"issue":"3","key":"2026081910214618700_cit24","doi-asserted-by":"publisher","DOI":"10.1002\/pep2.24057","article-title":"Bridged bicyclic\npeptides: Structure and function","volume":"110","author":"Thombare","year":"2018","journal-title":"Pept. Sci."},{"issue":"7","key":"2026081910214618700_cit25","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1002\/cmdc.201200071","article-title":"Bicyclic peptides with\noptimized ring size inhibit\nhuman plasma kallikrein and its orthologues while sparing paralogous\nproteases","volume":"7","author":"Baeriswyl","year":"2012","journal-title":"ChemMedchem"},{"issue":"2","key":"2026081910214618700_cit26","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.6800","article-title":"RGD peptide\nin cancer targeting: Benefits, challenges,\nsolutions, and possible integrin-RGD interactions","volume":"13","author":"Javid","year":"2024","journal-title":"Cancer Med."},{"issue":"5","key":"2026081910214618700_cit27","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1002\/bip.21422","article-title":"Circular proteins\nand mechanisms of cyclization","volume":"94","author":"Conlan","year":"2010","journal-title":"Biopolymers"},{"issue":"3","key":"2026081910214618700_cit28","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1006\/meth.2001.1187","article-title":"Intein-mediated ligation and cyclization\nof expressed proteins","volume":"24","author":"Xu","year":"2001","journal-title":"Methods"},{"issue":"18","key":"2026081910214618700_cit29","doi-asserted-by":"publisher","first-page":"3983","DOI":"10.1039\/D1OB00411E","article-title":"Approaches\nfor peptide and protein\ncyclisation","volume":"19","author":"Hayes","year":"2021","journal-title":"Org. Biomol. Chem."},{"issue":"6508","key":"2026081910214618700_cit30","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1126\/science.abb8330","article-title":"A defined\nstructural unit enables de novo design ofsmall-molecule\u2013binding\nproteins","volume":"369","author":"Polizzi","year":"2020","journal-title":"Science"},{"key":"2026081910214618700_cit31","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.1038\/s41551-025-01404-w","article-title":"Rapid\nclearance of achiral small-molecule\ndrugs using de novo-designed proteins and their cyclic and mirror-image\nvariants","volume":"9","author":"Chen","year":"2025","journal-title":"Nat. Biomed. Eng."},{"key":"2026081910214618700_cit32","doi-asserted-by":"publisher","DOI":"10.1101\/2024.10.10.615955","article-title":"Chai-1: Decoding the molecular interactions\nof life","author":"Discovery","year":"2024","journal-title":"bioRxiv"}],"container-title":["Journal of the American\nChemical Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jacs.6c09712","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/32\/34687\/66419330\/jacs.6c09712.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/32\/34687\/66419330\/jacs.6c09712.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T14:21:57Z","timestamp":1787149317000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jacsat\/article\/148\/32\/34687\/5246546\/Synergistic-Copper-Organoboron-Activation-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":32,"journal-issue":{"issue":"32","published-online":{"date-parts":[[2026,8,5]]},"published-print":{"date-parts":[[2026,8,19]]}},"URL":"https:\/\/doi.org\/10.1021\/jacs.6c09712","relation":{},"ISSN":["0002-7863","1520-5126"],"issn-type":[{"value":"0002-7863","type":"print"},{"value":"1520-5126","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]}}}