{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T23:41:25Z","timestamp":1762299685853,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T00:00:00Z","timestamp":1613952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hainan Provincial Natural Science Foundation of China","award":["No. 219QN150"],"award-info":[{"award-number":["No. 219QN150"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 81872794"],"award-info":[{"award-number":["No. 81872794"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Scientific Research Foundation of Hainan University","award":["No. KYQD(ZR)1918"],"award-info":[{"award-number":["No. KYQD(ZR)1918"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>\u03b1-Conotoxin TxIB, a selective antagonist of \u03b16\/\u03b13\u03b22\u03b23 nicotinic acetylcholine receptor, could be a potential therapeutic agent for addiction and Parkinson\u2019s disease. As a peptide with a complex pharmacophoric conformation, it is important and difficult to find a modifiable site which can be modified effectively and efficiently without activity loss. In this study, three xylene scaffolds were individually reacted with one pair of the cysteine residues ([1,3] or [2,4]), and iodine oxidation was used to form a disulfide bond between the other pair. Overall, six analogs were synthesized with moderate isolated yields from 55% to 65%, which is four times higher than the traditional two-step oxidation with orthogonal protection on cysteines. The cysteine [2,4] modified analogs, with higher stability in human serum than native TxIB, showed obvious inhibitory effect and selectivity on \u03b16\/\u03b13\u03b22\u03b23 nicotinic acetylcholine receptors (nAChRs), which was 100 times more than the cysteine [1,3] modified ones. This result demonstrated that the cysteine [2,4] disulfide bond is a new modifiable site of TxIB, and further modification can be a simple and feasible strategy for the exploitation and utilization of \u03b1-Conotoxin TxIB in drug discovery.<\/jats:p>","DOI":"10.3390\/md19020119","type":"journal-article","created":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T03:34:47Z","timestamp":1613964887000},"page":"119","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cysteine [2,4] Disulfide Bond as a New Modifiable Site of \u03b1-Conotoxin TxIB"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6835-6634","authenticated-orcid":false,"given":"Baojian","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maomao","family":"Ren","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Xiong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haonan","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Wu","sequence":"additional","affiliation":[{"name":"Medical School, Guangxi University, Nanning 530004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Fu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongting","family":"Zhangsun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China"},{"name":"Medical School, Guangxi University, Nanning 530004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5377-2034","authenticated-orcid":false,"given":"Shuai","family":"Dong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-5970","authenticated-orcid":false,"given":"Sulan","family":"Luo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China"},{"name":"Medical School, Guangxi University, Nanning 530004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.tips.2006.07.004","article-title":"Brain nicotinic acetylcholine receptors: Native subtypes and their relevance","volume":"27","author":"Gotti","year":"2006","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.neuroscience.2015.03.040","article-title":"Evidence for a role for alpha6* nAChRs in l-dopa-induced dyskinesias using Parkinsonian alpha6* nAChR gain-of-function mice","volume":"295","author":"Bordia","year":"2015","journal-title":"Neuroscience"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.neuropharm.2017.06.028","article-title":"alpha6beta2 subunit containing nicotinic acetylcholine receptors exert opposing actions on rapid dopamine signaling in the nucleus accumbens of rats with high-versus low-response to novelty","volume":"126","author":"Siciliano","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1111\/adb.12559","article-title":"alpha6 subunit-containing nicotinic receptors mediate low-dose ethanol effects on ventral tegmental area neurons and ethanol reward","volume":"23","author":"Steffensen","year":"2018","journal-title":"Addict. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/aps.2009.63","article-title":"Mysterious alpha6-containing nAChRs: Function, pharmacology, and pathophysiology","volume":"30","author":"Yang","year":"2009","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5815","DOI":"10.1021\/cr400401e","article-title":"Discovery, synthesis, and structure-activity relationships of conotoxins","volume":"114","author":"Akondi","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"107691","DOI":"10.1016\/j.neuropharm.2019.107691","article-title":"\u03b1-Conotoxin VnIB from Conus ventricosus is a potent and selective antagonist of \u03b16\u03b24* nicotinic acetylcholine receptors","volume":"157","author":"Valdes","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9256","DOI":"10.1021\/acs.jmedchem.8b00967","article-title":"Single Amino Acid Substitution in alpha-Conotoxin TxID Reveals a Specific alpha3beta4 Nicotinic Acetylcholine Receptor Antagonist","volume":"61","author":"Yu","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"E4026","DOI":"10.1073\/pnas.1503617112","article-title":"Cloning, synthesis, and characterization of alphaO-conotoxin GeXIVA, a potent alpha9alpha10 nicotinic acetylcholine receptor antagonist","volume":"112","author":"Luo","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1080\/10717544.2018.1436097","article-title":"alpha-Conotoxin ImI-modified polymeric micelles as potential nanocarriers for targeted docetaxel delivery to alpha7-nAChR overexpressed non-small cell lung cancer","volume":"25","author":"Mei","year":"2018","journal-title":"Drug Deliv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10032","DOI":"10.1021\/acs.chemrev.8b00789","article-title":"Heteroaryl Rings in Peptide Macrocycles","volume":"119","author":"Smolyar","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10113","DOI":"10.1002\/chem.202002468","article-title":"Disulfide Bond Replacement with 1,4- and 1,5-Disubstituted [1\u20133]-Triazole on C-X-C Chemokine Receptor Type 4 (CXCR4) Peptide Ligands: Small Changes that Make Big Differences","volume":"26","author":"Tomassi","year":"2020","journal-title":"Chem. Eur. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3959","DOI":"10.1002\/chem.201706149","article-title":"Bioconjugation with Thiols by Benzylic Substitution","volume":"24","author":"Watanabe","year":"2018","journal-title":"Chemistry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4059","DOI":"10.1039\/C5OB00160A","article-title":"Replacement of the CysA7-CysB7 disulfide bond with a 1,2,3-triazole linker causes unfolding in insulin glargine","volume":"13","author":"Williams","year":"2015","journal-title":"Org. Biomol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7368","DOI":"10.1039\/C7SC02420G","article-title":"A novel peptide stapling strategy enables the retention of ring-closing amino acid side chains for the Wnt\/beta-catenin signalling pathway","volume":"8","author":"Wu","year":"2017","journal-title":"Chem. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4810","DOI":"10.1002\/anie.201806009","article-title":"Arylation Chemistry for Bioconjugation","volume":"58","author":"Zhang","year":"2019","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1002\/med.21540","article-title":"Recent structural advances in constrained helical peptides","volume":"39","author":"Skowron","year":"2019","journal-title":"Med. Res. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4257","DOI":"10.1039\/C6SC05454D","article-title":"Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation","volume":"8","author":"Rojas","year":"2017","journal-title":"Chem. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15628","DOI":"10.1021\/jacs.7b09790","article-title":"Perfluoroarene-Based Peptide Macrocycles to Enhance Penetration Across the Blood-Brain Barrier","volume":"139","author":"Fadzen","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4972","DOI":"10.1021\/acs.orglett.7b02464","article-title":"Divinylsulfonamides as Specific Linkers for Stapling Disulfide Bonds in Peptides","volume":"19","author":"Li","year":"2017","journal-title":"Org. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1021\/cb4002393","article-title":"Dicarba alpha-conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAB receptors","volume":"8","author":"Robinson","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1021\/jm8011504","article-title":"Structure and Activity of (2,8)-Dicarba-(3,12)-cystino \u03b1-ImI, an \u03b1-Conotoxin Containing a Nonreducible Cystine Analogue","volume":"52, 3","author":"MacRaild","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11510","DOI":"10.1021\/acs.chemrev.9b00207","article-title":"Conotoxins: Chemistry and Biology","volume":"119","author":"Jin","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kennedy, A.C., Belgi, A., Husselbee, B.W., Spanswick, D., Norton, R.S., and Robinson, A.J. (2020). alpha-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia. Toxins, 12.","DOI":"10.3390\/toxins12080505"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1039\/C8SC04198A","article-title":"\u03b1-Conotoxin GI triazole-peptidomimetics: Potent and stable blockers of a human acetylcholine receptor","volume":"10","author":"Knuhtsen","year":"2019","journal-title":"Chem. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1002\/anie.201409678","article-title":"Stabilization of the cysteine-rich conotoxin MrIA by using a 1,2,3-triazole as a disulfide bond mimetic","volume":"54","author":"Gori","year":"2015","journal-title":"Angew Chem. Int. Ed. Engl."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1074\/jbc.M112.427898","article-title":"Characterization of a novel alpha-conotoxin from conus textile that selectively targets alpha6\/alpha3beta2beta3 nicotinic acetylcholine receptors","volume":"288","author":"Luo","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"You, S., Li, X., Xiong, J., Zhu, X., Zhangsun, D., Zhu, X., and Luo, S. (2019). alpha-Conotoxin TxIB: A Uniquely Selective Ligand for alpha6\/alpha3beta2beta3 Nicotinic Acetylcholine Receptor Attenuates Nicotine-Induced Conditioned Place Preference in Mice. Mar. Drugs, 17.","DOI":"10.3390\/md17090490"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3537","DOI":"10.3390\/md11093537","article-title":"Optimal cleavage and oxidative folding of alpha-conotoxin TxIB as a therapeutic candidate peptide","volume":"11","author":"Wu","year":"2013","journal-title":"Mar. Drugs"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/cbdd.13104","article-title":"Expression in Escherichia coli of fusion protein comprising alpha-conotoxin TxIB and preservation of selectivity to nicotinic acetylcholine receptors in the purified product","volume":"91","author":"Yu","year":"2018","journal-title":"Chem. Biol. Drug. Des."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Li, X., Wang, S., Zhu, X., Zhangsun, D., Wu, Y., and Luo, S. (2020). Effects of Cyclization on Activity and Stability of alpha-Conotoxin TxIB. Mar. Drugs, 18.","DOI":"10.3390\/md18040180"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/s41557-018-0042-7","article-title":"Cyclization of peptides with two chemical bridges affords large scaffold diversities","volume":"10","author":"Kale","year":"2018","journal-title":"Nat. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1002\/bip.20853","article-title":"Protein secondary structure analyses from circular dichroism spectroscopy: Methods and reference databases","volume":"89","author":"Whitmore","year":"2008","journal-title":"Biopolymers"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9933","DOI":"10.1021\/jm501126u","article-title":"Dicarba analogues of alpha-conotoxin RgIA. Structure, stability, and activity at potential pain targets","volume":"57","author":"Chhabra","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1006\/abio.2000.4879","article-title":"Estimation of protein secondary structure from circular dichroism spectra: Inclusion of denatured proteins with native proteins in the analysis","volume":"287","author":"Sreerama","year":"2000","journal-title":"Anal. Biochem."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/19\/2\/119\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:27:37Z","timestamp":1760160457000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/19\/2\/119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,22]]},"references-count":35,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["md19020119"],"URL":"https:\/\/doi.org\/10.3390\/md19020119","relation":{},"ISSN":["1660-3397"],"issn-type":[{"type":"electronic","value":"1660-3397"}],"subject":[],"published":{"date-parts":[[2021,2,22]]}}}