Uric Acid Crystallization Interrupted with Competing Binding Agents
Uric Acid Crystallization Interrupted with Competing Binding Agents
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DOI：
10.1021/acs.cgd.9b01225
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发表时间：
2019-12-01
影响因子：
3.8
通讯作者：
Swift, Jennifer A.
中科院分区：
文献类型：
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作者：
Hall, Victoria M.;Thornton, Alyssa;Swift, Jennifer A.
人体中的尿酸结晶与不期望的医学状况1600相关-包括痛风沉积物和肾结石的形成。尿酸生物矿化的一个主要因素，最常见的是尿酸盐（MSU）或无水尿酸（UA），是其在生理溶液中相对较低的溶解度。使用设计用于破坏在主要生理形式中观察到的结合基序的二齿和三齿结合模式，鉴定了几种杂环，其（1）显著延迟可见尿酸晶体出现所需的时间和/或（2）产生新的1：1尿酸共晶相。获得的所有五个新相都表现出组分之间的多齿氢键基序。荧光分析表明，三种共晶的可溶性比天然形式高3- 6倍。同样的竞争性结合方法随后扩展到甲氧苄啶，一种FDA批准的药物，具有与最有效的结合剂相同的子结构。添加甲氧苄啶尿酸溶液显着延迟结晶时间，也产生了一个新的共晶形式的溶解度大于MSU。这些结果有助于说明重新利用现有药物治疗尿酸疾病的潜在益处。
Uric acid crystallization in humans is associated with undesirable medical conditions 1600 - including the formation of gout deposits and kidney stones. A major contributing factor to uric acid biomineralization, most often as either monosodium urate (MSU) or anhydrous uric acid (UA), is its relatively low solubility in physiologic solutions. Using bidentate and tridentate binding patterns designed to disrupt the binding motifs observed in the major physiologic forms, several heterocycles were identified which (1) significantly delay the time required for visible uric acid crystals to appear and/or (2) yield new 1:1 uric acid cocrystal phases. All five of the new phases obtained exhibited a multidentate hydrogen bonding motif between components. Fluorescence assays showed that three of the cocrystals were 3-6x more soluble than the natural forms. The same competitive-binding approach was then extended to trimethoprim, an FDA-approved drug with the same substructure as the most effective binding agents. Addition of trimethoprim to uric acid solutions significantly delayed the crystallization times and also yielded a new cocrystal form with a solubility greater than MSU. These results serve to illustrate the potential benefits of repurposing existing pharmaceuticals to treat uric acid diseases.