{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:55:04Z","timestamp":1790733304248,"version":"4.1.0"},"reference-count":71,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["I01BX004939"],"award-info":[{"award-number":["I01BX004939"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["IK6BX006800"],"award-info":[{"award-number":["IK6BX006800"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["M2026001F"],"award-info":[{"award-number":["M2026001F"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30EY034070"],"award-info":[{"award-number":["P30EY034070"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"abstract":"<jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>Retinol\u2010binding protein 4 (RBP4) is a member of the lipocalin superfamily that is connected to disease states such as insulin resistance, fatty liver disease and ocular disorders including Stargardt disease. Several retinoid and non\u2010retinoid antagonists of this protein have been developed for potential clinical use, but none have yet received FDA approval. Tinlarebant, a derivative of the early lead RBP4 antagonist, A1120, was reported to slow macular lesion growth in Stargardt disease patients. However, its precise mechanism of RBP4 antagonism remains undisclosed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>The binding of tinlarebant to RBP4 was studied with fluorescence spectroscopy and crystallography. The impact of tinlarebant occupancy in the RBP4 retinol\u2010binding pocket on RBP4 complexation with transthyretin (TTR) was studied by size\u2010exclusion chromatography. The impact of tinlarebant on plasma RBP4 levels was studied in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Fluorescence quenching assays demonstrate that tinlarebant competitively displaces retinol from holo\u2010RBP4 with an IC\n                      <jats:sub>50<\/jats:sub>\n                      of 8.75\u2009\u00b1\u20090.38\u2009nM. The RBP4\u2010tinlarebant complex fails to associate with transthyretin\n                      <jats:italic>in vitro<\/jats:italic>\n                      . Administration of single doses of tinlarebant to mice reduced plasma RBP4 levels by up to 93%. The crystal structure shows that tinlarebant impedes RBP4 association with transthyretin through both conformational and steric effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Tinlarebant is a tight\u2010binding RBP4 antagonist that lowers RBP4 plasma levels due to disruption of the RBP4\u2010 transthyretin interaction. The crystal structure shows that tinlarebant integrates multiple aspects of RBP4 interaction and antagonism found in its predecessors. Together, these data illuminate the pharmacology of a clinical inhibitor of the RBP4\u2010retinol transport system.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70687","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:56:36Z","timestamp":1790729796000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structural and biochemical basis for retinol\u2010binding protein 4 antagonism by tinlarebant"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0048-0203","authenticated-orcid":false,"given":"Marco","family":"Bassetto","sequence":"first","affiliation":[{"name":"Gavin Herbert Eye Institute\u2014Brunson Center for Translational Vision Research, Department of Ophthalmology and Visual Sciences University of California Irvine  Irvine California USA"},{"name":"Research Service Tibor Rubin VA Long Beach Medical Center  Long Beach California USA"},{"name":"Department of Physiology &amp; Biophysics University of California Irvine  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1184-9539","authenticated-orcid":false,"given":"Philip D.","family":"Kiser","sequence":"additional","affiliation":[{"name":"Gavin Herbert Eye Institute\u2014Brunson Center for Translational Vision Research, Department of Ophthalmology and Visual Sciences University of California Irvine  Irvine California USA"},{"name":"Research Service Tibor Rubin VA Long Beach Medical Center  Long Beach California USA"},{"name":"Department of Physiology &amp; Biophysics University of California Irvine  Irvine California USA"},{"name":"Department of Clinical Pharmacy Practice University of California Irvine  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.369132"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/gbe\/evr084"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70229"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0397-236"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu258"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0378-1119(02)00754-0"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(92)81046-o"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1210\/edrv-10-3-308"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ctdb.2024.10.001"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-2836(03)00468-6"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(73)90196-2"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc06-0360"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.03.006"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm5010013"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c00996"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00423"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00352"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2020.100861"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/51.6.1082"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.12-10050"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.mie.2022.05.004"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)39396-2"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa054862"},{"issue":"7","key":"e_1_2_11_27_1","article-title":"Safety, tolerability, and efficacy of tinlarebant from the 24\u2010month phase 2 study in adolescent patients affected by Stargardt disease","volume":"65","author":"Grigg J. R.","year":"2024","journal-title":"Investigative Ophthalmology & Visual Science"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00604.x"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909047374"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909047337"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI105889"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1136244"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801060200"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.113856"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-11-0431"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b01963"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/BPH.15178"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1097\/IAE.0b013e318265801d"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889807021206"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102722"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M809654200"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444911001314"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1984.tb01995.x"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00468a012"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2580349"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.1.3.3622999"},{"key":"e_1_2_11_48_1","unstructured":"Petrukhin K. Cioffi C. Johnson G. Allikmets R. Freeman E. Chen P. &Zhu L.(2017).Substituted 4\u2010phenylpiperidines their preparation and use."},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.70009"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202403090R"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.05-0820"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2011.08.006"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/123.9.1497"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"issue":"1","key":"e_1_2_11_55_1","first-page":"3","article-title":"Phenotype in retinol deficiency due to a hereditary defect in retinol binding protein synthesis","volume":"40","author":"Seeliger M. W.","year":"1999","journal-title":"Investigative Ophthalmology & Visual Science"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)41584-6"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.8b01070"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5c00880"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/122.10.1999"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2011.12.001"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc06-2342"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.659977"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0286"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)46017-6"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi0268551"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2014.04.089"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3330"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1006\/prep.1998.0944"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03711"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2025.101360"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2008.06705.x"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)43925-7"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.70687","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bph.70687","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.70687","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:56:38Z","timestamp":1790729798000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.70687"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":71,"alternative-id":["10.1111\/bph.70687"],"URL":"https:\/\/doi.org\/10.1111\/bph.70687","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"assertion":[{"value":"2026-07-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"bph.70687"}}