Liu Yonghai, Zhang Pengfei, Lei Peiyun, Jin Yige, Yu Haoting, Zhang Xingde, Pan Yonglan, Ou Chunyan, Fu Tingming
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, PR China.
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, PR China.
Colloids Surf B Biointerfaces. 2024 Apr;236:113803. doi: 10.1016/j.colsurfb.2024.113803. Epub 2024 Feb 15.
The core to the treatment of gout is the elimination of pathologic crystal, monosodium urate monohydrate (MSUM). The primary treatment available is to gradually dissolve the "culprit crystals" by lowering the blood uric acid concentration with medications, which often takes a long time and in severe cases must still be treated surgically. Herein, we developed a dynamic bionic platform based on a hydrogel composite membrane (HCM) to screen the direct facilitated solubilization of MSUM crystals by small organic molecules in bionic saturated, or even supersaturated, solutions. The customized and biologically safe (NAGA/PEGDA/NIPAM) HCM, which is consistent with the main amino acid composition of articular cartilage, well mimics the entire process of organic molecules leading to the dissolution of MSUM crystals in the joint system. With the verifications of this platform, it is shown that l-aspartic acid (ASP) significantly promotes the dissolution of MSUM crystals not only in saturated but also in supersaturated solutions. Furthermore, a novel mechanism called "crane effect" was used to explain this "dissolution effect" of ASP on MSUM, which stems from the ability of ASP to lock onto the surface of MSUM crystals through hydrogen bonding by virtue of its two carboxyl groups, and simultaneously its amino group lifts the uric acid molecules from the surface of MSUM crystals by virtue of interactions of hydrogen bonding. The results of bulk crystallization, scanning electron microscopy (SEM), powder X-diffraction (PXRD), and density-functional theory (DFT) studies are quantitatively consistent with this hypothetical "crane effect" mechanism. Hence, this HCM-based functional platform could provide entirely novel ideas and methods for drug design and screening for the treatment of pathological crystal diseases of gout.
痛风治疗的核心是消除病理性晶体——单水尿酸钠（MSUM）。现有的主要治疗方法是通过药物降低血尿酸浓度来逐渐溶解“罪魁祸首晶体”，这通常需要很长时间，而且在严重情况下仍必须进行手术治疗。在此，我们开发了一种基于水凝胶复合膜（HCM）的动态仿生平台，用于筛选在仿生饱和甚至过饱和溶液中小有机分子对MSUM晶体的直接促溶作用。定制的、生物安全的（NAGA/PEGDA/NIPAM）HCM与关节软骨的主要氨基酸组成一致，很好地模拟了有机分子导致MSUM晶体在关节系统中溶解的整个过程。通过该平台的验证，结果表明L-天冬氨酸（ASP）不仅能显著促进MSUM晶体在饱和溶液中，而且能在过饱和溶液中的溶解。此外，还利用一种名为“起重机效应”的新机制来解释ASP对MSUM的这种“溶解效应”，这源于ASP凭借其两个羧基通过氢键锁定在MSUM晶体表面的能力，同时其氨基凭借氢键相互作用将尿酸分子从MSUM晶体表面提起。大量结晶、扫描电子显微镜（SEM）、粉末X射线衍射（PXRD）和密度泛函理论（DFT）研究的结果在定量上与这种假设的“起重机效应”机制一致。因此，这种基于HCM的功能平台可为痛风病理性晶体疾病治疗的药物设计和筛选提供全新的思路和方法。
