{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T01:56:55Z","timestamp":1794448615053,"version":"4.9.1"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,4,6]],"date-time":"2017-04-06T00:00:00Z","timestamp":1491436800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,4,6]],"date-time":"2017-04-06T00:00:00Z","timestamp":1491436800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Gout is caused by elevated serum urate levels, which can be treated using inhibitors of the uric acid transporter, URAT1. Here, we characterize verinurad (RDEA3170), which is currently under evaluation for gout therapy. Verinurad specifically inhibits URAT1 with a potency of 25\u2009nM. High affinity inhibition of uric acid transport requires URAT1 residues Cys-32, Ser-35, Phe-365 and Ile-481. Unlike other available uricosuric agents, the requirement for Cys-32 is unique to verinurad. Two of these residues, Ser-35 and Phe-365, are also important for urate transport kinetics. A URAT1 binding assay using radiolabeled verinurad revealed that distinct URAT1 inhibitors benzbromarone, sulfinpyrazone and probenecid all inhibit verinurad binding via a competitive mechanism. However, mutations made within the predicted transporter substrate channel differentially altered the potency for individual URAT1 inhibitors. Overall, our results suggest that URAT1 inhibitors bind to a common site in the core of the transporter and sterically hinder the transit of uric acid through the substrate channel, albeit with vastly different potencies and with differential interactions with specific URAT1 amino acids.<\/jats:p>","DOI":"10.1038\/s41598-017-00706-7","type":"journal-article","created":{"date-parts":[[2017,3,31]],"date-time":"2017-03-31T08:32:05Z","timestamp":1490949125000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":108,"title":["Discovery and characterization of verinurad, a potent and specific inhibitor of URAT1 for the treatment of hyperuricemia and gout"],"prefix":"10.1038","volume":"7","author":[{"given":"Philip K.","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmir","family":"Gunic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey N.","family":"Miner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,4,6]]},"reference":[{"key":"706_CR1","doi-asserted-by":"publisher","first-page":"499","DOI":"10.7326\/0003-4819-143-7-200510040-00009","volume":"143","author":"HK Choi","year":"2005","unstructured":"Choi, H. K., Mount, D. B. & Reginato, A. M. Pathogenesis of gout. Ann. Intern. Med \n                           143, 499\u2013516, doi:10.7326\/0003-4819-143-7-200510040-00009 (2005).","journal-title":"Ann. Intern. Med"},{"key":"706_CR2","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1056\/NEJMcp1001124","volume":"364","author":"T Neogi","year":"2011","unstructured":"Neogi, T. Clinical practice. Gout. N Engl J Med \n                           364, 443\u2013452, doi:10.1056\/NEJMcp1001124 (2011).","journal-title":"Gout. N Engl J Med"},{"key":"706_CR3","doi-asserted-by":"publisher","first-page":"3763","DOI":"10.1073\/pnas.1320393111","volume":"111","author":"JT Kratzer","year":"2014","unstructured":"Kratzer, J. T. et al. Evolutionary history and metabolic insights of ancient mammalian uricases. Proc. Natl. Acad. Sci. USA \n                           111, 3763\u20133768, doi:10.1073\/pnas.1320393111 (2014).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"706_CR4","doi-asserted-by":"publisher","first-page":"2193","DOI":"10.1093\/molbev\/msw116","volume":"33","author":"PK Tan","year":"2016","unstructured":"Tan, P. K., Farrar, J. E., Gaucher, E. A. & Miner, J. N. Coevolution of URAT1 and uricase during primate evolution: implications for serum urate homeostasis and gout. Mol. Biol. Evol. \n                           33, 2193\u2013200, doi:10.1093\/molbev\/msw116. (2016).","journal-title":"Mol. Biol. Evol."},{"key":"706_CR5","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1136\/ard.39.2.173","volume":"39","author":"DJ Levinson","year":"1980","unstructured":"Levinson, D. J. & Sorensen, L. B. Renal handling of uric acid in normal and gouty subject: evidence for a 4-component system. Ann. Rheum. Dis \n                           39, 173\u2013179, doi:10.1136\/ard.39.2.173 (1980).","journal-title":"Ann. Rheum. Dis"},{"key":"706_CR6","first-page":"80","volume":"14","author":"F Roch-Ramel","year":"1999","unstructured":"Roch-Ramel, F. & Guisan, B. Renal transport of urate in humans. News Physiol. Sci. \n                           14, 80\u201384 (1999).","journal-title":"News Physiol. Sci."},{"key":"706_CR7","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.jbspin.2016.04.007","volume":"84","author":"S Liu","year":"2016","unstructured":"Liu, S., Perez-Ruiz, F. & Miner, J. N. Patients with gout differ from healthy subjects in renal response to changes in serum uric acid. Joint Bone Spine \n                           84, 183\u2013188, doi:10.1016\/j.jbspin.2016.04.007. (2016).","journal-title":"Joint Bone Spine"},{"key":"706_CR8","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1038\/nature742","volume":"417","author":"A Enomoto","year":"2002","unstructured":"Enomoto, A. et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature \n                           417, 447\u2013452, doi:10.1038\/nature742 (2002).","journal-title":"Nature"},{"key":"706_CR9","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1097\/BOR.0000000000000035","volume":"26","author":"MH Bach","year":"2014","unstructured":"Bach, M. H. & Simkin, P. A. Uricosuric drugs: the once and future therapy for hyperuricemia? Curr Opin Rheumatol \n                           26, 169\u2013175, doi:10.1097\/BOR.0000000000000035 (2014).","journal-title":"Curr Opin Rheumatol"},{"key":"706_CR10","doi-asserted-by":"publisher","first-page":"2167","DOI":"10.1093\/rheumatology\/ket487","volume":"53","author":"R Fleischmann","year":"2014","unstructured":"Fleischmann, R. et al. Pharmacodynamic, pharmacokinetic and tolerability evaluation of concomitant administration of lesinurad and febuxostat in gout patients with hyperuricaemia. Rheumatology. (Oxford) \n                           53, 2167\u20132174, doi:10.1093\/rheumatology\/ket487 (2014).","journal-title":"Rheumatology. (Oxford)"},{"key":"706_CR11","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1007\/s40265-016-0550-y","volume":"76","author":"SM Hoy","year":"2016","unstructured":"Hoy, S. M. Lesinurad: first global approval. Drugs \n                           76, 509\u2013516, doi:10.1007\/s40265-016-0550-y (2016).","journal-title":"Drugs"},{"key":"706_CR12","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1186\/s13075-016-1107-x","volume":"18","author":"JN Miner","year":"2016","unstructured":"Miner, J. N. et al. Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney. Arthritis Res Ther \n                           18, 214, doi:10.1186\/s13075-016-1107-x (2016).","journal-title":"Arthritis Res Ther"},{"key":"706_CR13","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1136\/annrheumdis-2015-207919","volume":"75","author":"F Perez-Ruiz","year":"2016","unstructured":"Perez-Ruiz, F., Sundy, J. S., Miner, J. N., Cravets, M. & Storgard, C. Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol. Ann. Rheum. Dis \n                           75, 1074\u20131080, doi:10.1136\/annrheumdis-2015-207919 (2016).","journal-title":"Ann. Rheum. Dis"},{"key":"706_CR14","doi-asserted-by":"publisher","first-page":"3423","DOI":"10.2147\/DDDT.S85193","volume":"9","author":"Z Shen","year":"2015","unstructured":"Shen, Z. et al. Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males. Drug Des. Devel. Ther \n                           9, 3423\u20133434, doi:10.2147\/DDDT.S85193 (2015).","journal-title":"Drug Des. Devel. Ther"},{"key":"706_CR15","doi-asserted-by":"publisher","first-page":"34995","DOI":"10.1038\/srep34995","volume":"6","author":"PK Tan","year":"2016","unstructured":"Tan, P. K., Ostertag, T. M. & Miner, J. N. Mechanism of high affinity inhibition of the human urate transporter URAT1. Sci. Rep \n                           6, 34995, doi:10.1038\/srep34995 (2016).","journal-title":"Sci. Rep"},{"key":"706_CR16","doi-asserted-by":"publisher","first-page":"38071","DOI":"10.1074\/jbc.M608834200","volume":"281","author":"JL Perry","year":"2006","unstructured":"Perry, J. L., Dembla-Rajpal, N., Hall, L. A. & Pritchard, J. B. A three-dimensional model of human organic anion transporter 1: aromatic amino acids required for substrate transport. J Biol. Chem. \n                           281, 38071\u201338079, doi:10.1074\/jbc.M608834200 (2006).","journal-title":"J Biol. Chem."},{"key":"706_CR17","doi-asserted-by":"publisher","first-page":"13402","DOI":"10.1074\/jbc.M609849200","volume":"282","author":"AN Rizwan","year":"2007","unstructured":"Rizwan, A. N., Krick, W. & Burckhardt, G. The chloride dependence of the human organic anion transporter 1 (hOAT1) is blunted by mutation of a single amino acid. J Biol. Chem. \n                           282, 13402\u201313409, doi:10.1074\/jbc.M609849200 (2007).","journal-title":"J Biol. Chem."},{"key":"706_CR18","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1111\/j.1440-1797.2010.01368.x","volume":"16","author":"HJ Shin","year":"2011","unstructured":"Shin, H. J. et al. Interactions of urate transporter URAT1 in human kidney with uricosuric drugs. Nephrology. (Carlton.) \n                           16, 156\u2013162, doi:10.1111\/nep.2011.16.issue-2 (2011).","journal-title":"Nephrology. (Carlton.)"},{"key":"706_CR19","doi-asserted-by":"publisher","first-page":"1587","DOI":"10.1039\/C6MD00190D","volume":"7","author":"IA Storer","year":"2016","unstructured":"Storer, I. A. et al. The discovery and evaluation of diaryl ether heterocyclic sulfonamides as URAT1 inhibitors for the treatment of gout. Med. Chem. Commun. \n                           7, 1587\u20131595, doi:10.1039\/C6MD00190D (2016).","journal-title":"Med. Chem. Commun."},{"key":"706_CR20","doi-asserted-by":"publisher","first-page":"89","DOI":"10.2169\/internalmedicine.49.2597","volume":"49","author":"D Uetake","year":"2010","unstructured":"Uetake, D. et al. Effect of fenofibrate on uric acid metabolism and urate transporter 1. Intern. Med \n                           49, 89\u201394, doi:10.2169\/internalmedicine.49.2597 (2010).","journal-title":"Intern. 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Nature \n                           526, 397\u2013401, doi:10.1038\/nature14909 (2015).","journal-title":"Nature"},{"key":"706_CR26","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1007\/s12013-011-9191-7","volume":"61","author":"IF Tsigelny","year":"2011","unstructured":"Tsigelny, I. F. et al. Conformational changes of the multispecific transporter organic anion transporter 1 (OAT1\/SLC22A6) suggests a molecular mechanism for initial stages of drug and metabolite transport. Cell Biochem. Biophys. \n                           61, 251\u2013259, doi:10.1007\/s12013-011-9191-7 (2011).","journal-title":"Cell Biochem. Biophys."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00706-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00706-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00706-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T03:30:00Z","timestamp":1671766200000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00706-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,6]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["706"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-00706-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,6]]},"assertion":[{"value":"9 December 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 March 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 April 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"665"}}