Pharmacology and Pharmaceutical Sciences, University of Missouri-Kansas City School of Pharmacy, 2464 Charlotte St., Kansas City, MO, 64108.
Chembiochem. 2024 Nov 4;25(21):e202400319. doi: 10.1002/cbic.202400319. Epub 2024 Sep 9.
Pseudo-gout is caused by the deposition of highly insoluble calcium pyrophosphate dihydrate (CPPD) crystals in the joints of sufferers. This leads to inflammation and ultimately joint damage. The insolubility of CPPD is driven by the strong attraction of di-cationic calcium ions with tetra-anionic pyrophosphate ions. One of the challenges of dissolving CPPD is that a related mineral, hydroxy apatite (HA) is present in larger amounts in the form of bone and also contains strongly interacting calcium and phosphate ions. Our aim in this work was to selectively dissolve CPPD in preference to HA. To accomplish this, we used a known receptor for pyrophosphate that contains two complexed zinc ions that are ideally spaced to interact with the tetra-anion of pyrophosphate. We hypothesized that such a molecule could act as a preorganized tetra-cation that would be able to outcompete the two calcium ions present in the crystal lattice of CPPD. We demonstrate both visually and through analysis of released phosphorous that this molecule is able to preferentially dissolve CPPD over the closely related HA and thus can form the basis for a possible approach for the treatment of pseudo-gout.
假痛风是由患者关节中高度不溶性焦磷酸钙二水合物（CPPD）晶体的沉积引起的。这会导致炎症，最终导致关节损伤。CPPD 的不溶性是由二价阳离子钙离子与四价阴离子焦磷酸盐离子的强烈吸引力驱动的。溶解 CPPD 的挑战之一是，以骨的形式存在大量相关矿物质羟基磷灰石（HA），并且还含有相互作用强烈的钙和磷酸盐离子。我们在这项工作中的目标是选择性地溶解 CPPD 而不是 HA。为了实现这一目标，我们使用了一种已知的焦磷酸盐受体，其中包含两个配位的锌离子，这些锌离子理想地间隔开以与焦磷酸盐的四面体相互作用。我们假设这样的分子可以作为一个预先组织好的四面体，能够与 CPPD 晶格中存在的两个钙离子竞争。我们通过视觉和释放磷的分析证明，这种分子能够优先溶解 CPPD 而不是密切相关的 HA，因此可以作为治疗假痛风的可能方法的基础。
