Abstract
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.
Highlights
Gout is a metabolic disease caused by chronically elevated serum uric acid levels, leading to deposition of urate in the joints and acute bouts of painful inflammatory arthritis[1, 2]
We describe the molecular pharmacology of a novel, highly potent and specific URAT1 inhibitor, verinurad, that is currently under evaluation for the treatment of gout and asymptomatic hyperuricemia
Verinurad-mediated inhibition of URAT1 is highly dependent on human URAT1 Phe-365 and Ser-35, both of which are located in the substrate channel
Summary
Gout is a metabolic disease caused by chronically elevated serum uric acid (sUA) levels (hyperuricemia), leading to deposition of urate in the joints and acute bouts of painful inflammatory arthritis[1, 2]. Compared to individuals with normal sUA levels, most patients with gout exhibit reduced fractional excretion of uric acid (FEUA), leading to hyperuricemia[7]. We previously hypothesized that reduced FEUA could be due to altered URAT1 transport kinetics that increase renal urate reabsorption[7]. Benzbromarone, sulfinpyrazone, probenecid and lesinurad (Figure S1) are among a class of gout therapeutics that lower sUA levels by inhibiting URAT1 and enhancing FEUA. We describe the molecular pharmacology of a novel, highly potent and specific URAT1 inhibitor, verinurad ( known as RDEA3170; Figure S1), that is currently under evaluation for the treatment of gout and asymptomatic hyperuricemia. Ser-35 and Phe-365 are important in affinity for urate, suggesting that URAT1 inhibitors bind in the core of the transporter and sterically hinder the transit of uric acid through the substrate channel
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