{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T18:08:43Z","timestamp":1789236523175,"version":"build-2803163510"},"reference-count":132,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T00:00:00Z","timestamp":1645660800000},"content-version":"vor","delay-in-days":54,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81202394"],"award-info":[{"award-number":["81202394"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Oxidative Medicine and Cellular Longevity"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p>Overcoming blood\u2010brain barrier (BBB) to improve brain bioavailability of therapeutic drug remains an ongoing concern. Prodrug is one of the most reliable approaches for delivering agents with low\u2010level BBB permeability into the brain. The well\u2010known antioxidant capacities of cysteine (Cys) and its vital role in glutathione (GSH) synthesis indicate that Cys\u2010based prodrug could potentiate therapeutic drugs against oxidative stress\u2010related neurodegenerative disorders. Moreover, prodrug with Cys moiety could be recognized by the excitatory amino acid transporter 3 (EAAT3) that is highly expressed at the BBB and transports drug into the brain. In this review, we summarized the strategies of crossing BBB, properties of EAAT3 and its natural substrates, Cys and its donors, and Cys donor\u2010based brain\u2010targeting prodrugs by referring to recent investigations. Moreover, the challenges that we are faced with and future research orientations were also addressed and proposed. It is hoped that present review will provide evidence for the pursuit of novel Cys donor\u2010based brain\u2010targeting prodrug.<\/jats:p>","DOI":"10.1155\/2022\/4834117","type":"journal-article","created":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T19:50:46Z","timestamp":1645732246000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cysteine Donor\u2010Based Brain\u2010Targeting Prodrug: Opportunities and Challenges"],"prefix":"10.1155","volume":"2022","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8108-7982","authenticated-orcid":false,"given":"Gaoyang","family":"Ni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenbiao","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziteng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guihong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0226-5638","authenticated-orcid":false,"given":"Zhaowei","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9023-6591","authenticated-orcid":false,"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,2,24]]},"reference":[{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1159\/000516340"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.47.120505.105237"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2021.04.008"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11481-017-9725-x"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/1270256"},{"key":"e_1_2_9_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2020.04.006"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1080\/01616412.2016.1251711"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/134.3.489"},{"key":"e_1_2_9_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2018.10.007"},{"key":"e_1_2_9_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(99)00060-X"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2005.02.005"},{"key":"e_1_2_9_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0173(97)00045-3"},{"key":"e_1_2_9_13_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.52.070183.003431"},{"key":"e_1_2_9_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)41830-9"},{"key":"e_1_2_9_15_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-02-00562.1999"},{"key":"e_1_2_9_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(96)13217-1"},{"key":"e_1_2_9_17_2","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/136.1.218S"},{"key":"e_1_2_9_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2007.06.947"},{"key":"e_1_2_9_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/smll.201701921"},{"key":"e_1_2_9_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-016-0405-9"},{"key":"e_1_2_9_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2012.76"},{"key":"e_1_2_9_22_2","doi-asserted-by":"publisher","DOI":"10.2174\/1381612826666200116153912"},{"key":"e_1_2_9_23_2","doi-asserted-by":"publisher","DOI":"10.1177\/106002809502901107"},{"key":"e_1_2_9_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2004.11.029"},{"key":"e_1_2_9_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfh206"},{"key":"e_1_2_9_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2017.06.023"},{"key":"e_1_2_9_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2009.07.028"},{"key":"e_1_2_9_28_2","doi-asserted-by":"publisher","DOI":"10.1039\/c9cs00622b"},{"key":"e_1_2_9_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2468"},{"key":"e_1_2_9_30_2","doi-asserted-by":"publisher","DOI":"10.2174\/138161211798194486"},{"key":"e_1_2_9_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2014.05.072"},{"key":"e_1_2_9_32_2","doi-asserted-by":"publisher","DOI":"10.1080\/10717544.2018.1431978"},{"key":"e_1_2_9_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.201700382"},{"key":"e_1_2_9_34_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.9b00502"},{"key":"e_1_2_9_35_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules14093268"},{"key":"e_1_2_9_36_2","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2018.1502273"},{"key":"e_1_2_9_37_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm8015409"},{"key":"e_1_2_9_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.13.5779"},{"key":"e_1_2_9_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.119.316463"},{"key":"e_1_2_9_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemphyslip.2019.01.005"},{"key":"e_1_2_9_41_2","doi-asserted-by":"publisher","DOI":"10.4155\/tde.12.165"},{"key":"e_1_2_9_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2017.07.038"},{"key":"e_1_2_9_43_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20010027"},{"key":"e_1_2_9_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-012-1348-1"},{"key":"e_1_2_9_45_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.8b00697"},{"key":"e_1_2_9_46_2","doi-asserted-by":"publisher","DOI":"10.1023\/a:1007518525161"},{"key":"e_1_2_9_47_2","doi-asserted-by":"publisher","DOI":"10.2174\/1389200220666191021103018"},{"key":"e_1_2_9_48_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2007.05024.x"},{"key":"e_1_2_9_49_2","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-200108000-00005"},{"key":"e_1_2_9_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0024-3205(03)00504-6"},{"key":"e_1_2_9_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0306-4522(01)00147-6"},{"key":"e_1_2_9_52_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.45.31891"},{"key":"e_1_2_9_53_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20225671"},{"key":"e_1_2_9_54_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b00700"},{"key":"e_1_2_9_55_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm300345z"},{"key":"e_1_2_9_56_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00007.2013"},{"key":"e_1_2_9_57_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-015-1768-3"},{"key":"e_1_2_9_58_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2008.00186.x"},{"key":"e_1_2_9_59_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.591867"},{"key":"e_1_2_9_60_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18122596"},{"key":"e_1_2_9_61_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0109245"},{"key":"e_1_2_9_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2016.12.013"},{"key":"e_1_2_9_63_2","doi-asserted-by":"publisher","DOI":"10.1051\/mmnp\/2019020"},{"key":"e_1_2_9_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2018.05.012"},{"key":"e_1_2_9_65_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-013-1484-0"},{"key":"e_1_2_9_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/360467a0"},{"key":"e_1_2_9_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03018"},{"key":"e_1_2_9_68_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-006-0877-5"},{"key":"e_1_2_9_69_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja208485w"},{"key":"e_1_2_9_70_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1996.sp021393"},{"key":"e_1_2_9_71_2","doi-asserted-by":"publisher","DOI":"10.1093\/jas\/skz211"},{"key":"e_1_2_9_72_2","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.08r01cr"},{"key":"e_1_2_9_73_2","doi-asserted-by":"publisher","DOI":"10.1002\/smll.201704093"},{"key":"e_1_2_9_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2018.08.003"},{"key":"e_1_2_9_75_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-013-1481-5"},{"key":"e_1_2_9_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2012.05.019"},{"key":"e_1_2_9_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2019.100982"},{"key":"e_1_2_9_78_2","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/7092032"},{"key":"e_1_2_9_79_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules23123305"},{"key":"e_1_2_9_80_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-30272-5"},{"key":"e_1_2_9_81_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01373429"},{"key":"e_1_2_9_82_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-010-0593-4"},{"key":"e_1_2_9_83_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2006.12.010"},{"key":"e_1_2_9_84_2","doi-asserted-by":"publisher","DOI":"10.1080\/15563650.2020.1784428"},{"key":"e_1_2_9_85_2","doi-asserted-by":"publisher","DOI":"10.1006\/exer.1996.0048"},{"key":"e_1_2_9_86_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(24)39051-2"},{"key":"e_1_2_9_87_2","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/120.2.158"},{"key":"e_1_2_9_88_2","doi-asserted-by":"publisher","DOI":"10.18388\/abp.1997_4378"},{"key":"e_1_2_9_89_2","doi-asserted-by":"publisher","DOI":"10.1080\/10715762.2018.1468564"},{"key":"e_1_2_9_90_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0891-5849(98)00024-0"},{"key":"e_1_2_9_91_2","doi-asserted-by":"publisher","DOI":"10.1089\/aid.1994.10.961"},{"key":"e_1_2_9_92_2","doi-asserted-by":"publisher","DOI":"10.1007\/s002030050758"},{"key":"e_1_2_9_93_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4274(93)90140-s"},{"key":"e_1_2_9_94_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1998.tb04391.x"},{"key":"e_1_2_9_95_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2018.02.007"},{"key":"e_1_2_9_96_2","doi-asserted-by":"publisher","DOI":"10.3390\/nu11051056"},{"key":"e_1_2_9_97_2","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.3.5.2920877"},{"key":"e_1_2_9_98_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(89)91494-7"},{"key":"e_1_2_9_99_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.2000.01595.x"},{"key":"e_1_2_9_100_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2004.03.072"},{"key":"e_1_2_9_101_2","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.2001.2662"},{"key":"e_1_2_9_102_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0955-2863(02)00218-8"},{"key":"e_1_2_9_103_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1998.tb04435.x"},{"key":"e_1_2_9_104_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V961093"},{"key":"e_1_2_9_105_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M048223"},{"key":"e_1_2_9_106_2","first-page":"73","article-title":"L-2-oxothiazolidine-4-carboxylic acid attenuates oxidative stress and inflammation in retinal pigment epithelium","volume":"20","author":"Promsote W.","year":"2014","journal-title":"Molecular Vision"},{"key":"e_1_2_9_107_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510310219"},{"key":"e_1_2_9_108_2","doi-asserted-by":"publisher","DOI":"10.5483\/bmbrep.2012.45.6.276"},{"key":"e_1_2_9_109_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(96)00144-x"},{"key":"e_1_2_9_110_2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.158.4.9702043"},{"key":"e_1_2_9_111_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI1155"},{"key":"e_1_2_9_112_2","doi-asserted-by":"publisher","DOI":"10.1177\/089686080202200301"},{"key":"e_1_2_9_113_2","doi-asserted-by":"publisher","DOI":"10.1128\/cdli.4.3.352-357.1997"},{"key":"e_1_2_9_114_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1472-8206.2007.00495.x"},{"key":"e_1_2_9_115_2","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfl209"},{"key":"e_1_2_9_116_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M106439200"},{"key":"e_1_2_9_117_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.etp.2010.08.012"},{"key":"e_1_2_9_118_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-2212fje"},{"key":"e_1_2_9_119_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.105.016055"},{"key":"e_1_2_9_120_2","doi-asserted-by":"publisher","DOI":"10.1097\/00008390-200202000-00004"},{"key":"e_1_2_9_121_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2009.06.017"},{"key":"e_1_2_9_122_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-019-00707-w"},{"key":"e_1_2_9_123_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm701524h"},{"key":"e_1_2_9_124_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.22405"},{"key":"e_1_2_9_125_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm401883v"},{"key":"e_1_2_9_126_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2016.03.017"},{"key":"e_1_2_9_127_2","doi-asserted-by":"publisher","DOI":"10.7861\/clinmedicine.13-1-93"},{"key":"e_1_2_9_128_2","volume-title":"Medicinal Chemistry","author":"You Q.","year":"2016"},{"key":"e_1_2_9_129_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2020.131387"},{"key":"e_1_2_9_130_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2016.03.019"},{"key":"e_1_2_9_131_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules13051035"},{"key":"e_1_2_9_132_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules23061289"}],"container-title":["Oxidative Medicine and Cellular Longevity"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/downloads.hindawi.com\/journals\/omcl\/2022\/4834117.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/omcl\/2022\/4834117.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/2022\/4834117","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T00:32:12Z","timestamp":1748910732000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/2022\/4834117"}},"subtitle":[],"editor":[{"given":"Stefania","family":"Crispi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,1]]},"references-count":132,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,1]]}},"alternative-id":["10.1155\/2022\/4834117"],"URL":"https:\/\/doi.org\/10.1155\/2022\/4834117","archive":["Portico"],"relation":{},"ISSN":["1942-0900","1942-0994"],"issn-type":[{"value":"1942-0900","type":"print"},{"value":"1942-0994","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1]]},"assertion":[{"value":"2021-12-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"4834117"}}