{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:46:00Z","timestamp":1790736360437,"version":"4.1.0"},"reference-count":92,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T00:00:00Z","timestamp":1762560000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T00:00:00Z","timestamp":1762560000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>Relaxin\u20103 is a two\u2010chain neuropeptide of the insulin\/relaxin superfamily and the cognate ligand for the G protein\u2010coupled receptor RXFP3. Since its discovery, the relaxin\u20103\/RXFP3 signaling system has emerged as a key regulator of feeding behavior, stress responses, arousal, addiction, and cognitive function. Recent structural studies, including the first cryo\u2010electron microscopy structures of RXFP3 bound to relaxin\u20103 and small molecules, have provided significant insights into ligand\u2013receptor interactions. Together with mutagenesis and pharmacological studies, these advances have facilitated the design of diverse RXFP3 ligands, ranging from simplified and\/or stapled single\u2010chain analogs of relaxin\u20103 to grafted scaffolds and small\u2010molecule modulators. Such tools have been instrumental for probing relaxin\u20103 biology in\u2009vivo and highlight the system's therapeutic potential for treating anxiety, depression, obesity, binge eating, and alcohol use disorder. However, challenges remain, particularly regarding blood\u2013brain barrier penetration, receptor subtype selectivity, pharmacokinetic optimization, and safe long\u2010term modulation. This review summarizes current knowledge of relaxin\u20103 structure, receptor interactions, and pharmacology and highlights how advances in peptide chemistry, structural biology, and small\u2010molecule design are enabling the rational development of RXFP3\u2010targeted therapeutics.<\/jats:p>","DOI":"10.1002\/cbic.202500664","type":"journal-article","created":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T08:50:57Z","timestamp":1762591857000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["From Structure to Function: Development of Relaxin\u20103 Analogs and their Role in RXFP3 Signaling"],"prefix":"10.1002","volume":"27","author":[{"given":"Isabelle","family":"Riches","sequence":"first","affiliation":[{"name":"Florey Department of Neuroscience and Mental Health The University of Melbourne  Victoria 3052 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongkang","family":"Wu","sequence":"additional","affiliation":[{"name":"Florey Department of Neuroscience and Mental Health The University of Melbourne  Victoria 3052 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Predrag","family":"Kalaba","sequence":"additional","affiliation":[{"name":"Florey Department of Neuroscience and Mental Health The University of Melbourne  Victoria 3052 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish","family":"Sethi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology The University of Melbourne  Victoria 3052 Australia"},{"name":"Australian Nuclear Science Technology Organisation The Australian Synchrotron  800 Blackburn Road Clayton VIC 3168 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Lkhagvajargal","sequence":"additional","affiliation":[{"name":"Florey Department of Neuroscience and Mental Health The University of Melbourne  Victoria 3052 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Florey Department of Neuroscience and Mental Health The University of Melbourne  Victoria 3052 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Maslov","sequence":"additional","affiliation":[{"name":"Florey Department of Neuroscience and Mental Health The University of Melbourne  Victoria 3052 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross A. D.","family":"Bathgate","sequence":"additional","affiliation":[{"name":"Florey Department of Neuroscience and Mental Health The University of Melbourne  Victoria 3052 Australia"},{"name":"Department of Biochemistry and Pharmacology The University of Melbourne  Victoria 3052 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9961-0006","authenticated-orcid":false,"given":"Mohammed Akhter","family":"Hossain","sequence":"additional","affiliation":[{"name":"Florey Department of Neuroscience and Mental Health The University of Melbourne  Victoria 3052 Australia"},{"name":"School of Chemistry The University of Melbourne  Victoria 3052 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,8]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107882200"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13684"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2019.01.008"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2013.00013"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2148-5-14"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi020649b"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1282.078"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0083-6729(08)00601-8"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M005728200"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)50040-5"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107882200"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.22197"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2014.03.037"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2012.83"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.01114.x"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2005.03980.x"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2006.08.072"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13659"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.22442"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2016.00036"},{"key":"e_1_2_8_22_1","doi-asserted-by":"crossref","unstructured":"N.Nasirova L. A.Quina G.Morton A.Walker E. E.Turner eneuro 2020 7 ENEURO.0272\u20130220.2020.","DOI":"10.1523\/ENEURO.0272-20.2020"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00046"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1210\/mend.14.8.0510"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M308995200"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212457200"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M308996200"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M409916200"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2024.116714"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchemneu.2011.05.013"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2017.08.044"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2009.06.019"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-010-9468-0"},{"key":"e_1_2_8_34_1","doi-asserted-by":"crossref","unstructured":"P. J.Ryan H. E.Kastman E. V.Krstew K. J.Rosengren M. A.Hossain L.Churilov J. D.Wade A. L.Gundlach A. J.Lawrence Proceedings of the National Academy of Sciences of the United States of America 2013 110 20789\u201320794.","DOI":"10.1073\/pnas.1317807110"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.12155"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2021.637922"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP273787"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.106.032763"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.21895"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abl5880"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2895-19.2020"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M701416200"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2008.03790.x"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-025-08220-7"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c02743"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.0c00456"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800489200"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-03465-7"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801911200"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b00265"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2016.08.001"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14774"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines8100415"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116737"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00139-y"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja110567j"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.002611"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2020.00087"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2019.02.013"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm201505p"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.002645"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26247511"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr60225a003"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01081"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-020-0390-x"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00508"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15949"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5c00361"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36182-z"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2004-1532"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi052233e"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.104.006700"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2015.11.014"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2013.01.034"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-015-4131-7"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13955"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0122504"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2014.04.017"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-183X.2011.00730.x"},{"key":"e_1_2_8_80_1","first-page":"42","volume":"118","author":"Smith C. M.","year":"2013","journal-title":"Ital. J. Anat. Embryol."},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.16217"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.1101\/lm.1438109"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.22709"},{"key":"e_1_2_8_84_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01481-w"},{"key":"e_1_2_8_85_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2013.00128"},{"key":"e_1_2_8_86_1","doi-asserted-by":"publisher","DOI":"10.1080\/10799890600623373"},{"key":"e_1_2_8_87_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb500918v"},{"key":"e_1_2_8_88_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511210200"},{"key":"e_1_2_8_89_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560050806"},{"key":"e_1_2_8_90_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M603829200"},{"key":"e_1_2_8_91_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20082353"},{"key":"e_1_2_8_92_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_2_8_93_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-015-1961-x"}],"container-title":["ChemBioChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.202500664","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cbic.202500664","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.202500664","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T20:00:35Z","timestamp":1783108835000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cbic.202500664"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,8]]},"references-count":92,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/cbic.202500664"],"URL":"https:\/\/doi.org\/10.1002\/cbic.202500664","archive":["Portico"],"relation":{},"ISSN":["1439-4227","1439-7633"],"issn-type":[{"value":"1439-4227","type":"print"},{"value":"1439-7633","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,8]]},"assertion":[{"value":"2025-09-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202500664"}}