Department of Biology, Ardea Biosciences, Inc. (A member of the AstraZeneca Group), San Diego, CA, USA.
Department of Chemistry, Ardea Biosciences, Inc. (A member of the AstraZeneca Group), San Diego, CA, USA.
Sci Rep. 2017 Apr 6;7(1):665. doi: 10.1038/s41598-017-00706-7.
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 nM. 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.
痛风是由血清尿酸水平升高引起的，可以使用尿酸转运体 URAT1 的抑制剂进行治疗。在这里，我们对 verinurad（RDEA3170）进行了表征，它目前正在评估用于痛风治疗。Verinurad 对 URAT1 的抑制作用具有 25nM 的效力。尿酸转运的高亲和力抑制需要 URAT1 残基 Cys-32、Ser-35、Phe-365 和 Ile-481。与其他可用的促尿酸排泄药物不同，Cys-32 的要求是 verinurad 所特有的。这两个残基，Ser-35 和 Phe-365，对尿酸转运动力学也很重要。使用放射性标记的 verinurad 进行的 URAT1 结合测定表明，不同的 URAT1 抑制剂苯溴马隆、磺吡酮和丙磺舒均通过竞争性机制抑制 verinurad 结合。然而，在预测的转运体底物通道内进行的突变会以不同的方式改变对单个 URAT1 抑制剂的效力。总的来说，我们的结果表明，URAT1 抑制剂结合到转运体核心的一个共同位点，并通过空间位阻阻碍尿酸通过底物通道的转运，尽管它们的效力差异很大，并且与特定的 URAT1 氨基酸的相互作用也不同。
