Therapeutic Potential of Polyamidoamine Dendrimer for Amyloidogenic Transthyretin Amyloidosis
Therapeutic Potential of Polyamidoamine Dendrimer for Amyloidogenic Transthyretin Amyloidosis
复制标题
聚酰胺胺树枝状聚合物对淀粉样变性甲状腺素运载蛋白淀粉样变性的治疗潜力
DOI：
10.1021/acschemneuro.9b00059
复制
发表时间：
2019
影响因子：
5
通讯作者：
Arima H.
中科院分区：
文献类型：
--
作者：
Inoue M;Ueda M;Higashi T;Anno T;Fujisawa K;Motoyama K;Mizuguchi M;Ando Y;Jono H;Arima H.
淀粉样变性转甲状腺蛋白(ATTR)淀粉样变性是由形成ATTR淀粉样纤维引起的。由于ATTR的错误折叠会触发聚集体和淀粉样纤维的形成，而这些聚集体和淀粉样纤维被认为是沉积在组织上的，因此迫切需要针对这些过程的新的临床有效的治疗策略。在这项研究中，为了发现治疗ATTR淀粉样变性的新候选药物，我们将重点放在聚酰胺胺树状大分子(树状大分子)上，这是一种三维结构的纳米材料，它具有支化的阳离子聚合物重复的聚酰胺-胺单元。树状大分子(G2)不仅抑制ATTRV30M淀粉样纤维的形成，而且通过减少ATTRV30M蛋白的β-Sheet结构来减少已经形成的ATTRV30M淀粉样纤维。此外，静脉注射树枝状大分子(G2)减少了人ATTRV30M转基因大鼠的TTR沉积。这些结果表明，树枝状大分子(G2)可能对ATTRV30M淀粉样变性既有抑制作用又有破坏作用，提示树枝状大分子有可能作为一种双重有效的药物来对抗TTR淀粉样变性。
Amyloidogenic transthyretin (ATTR) amyloidosis is caused by a formation of ATTR amyloid fibrils. Because ATTR misfolding triggers the formation of aggregates and amyloid fibrils, which are considered to deposit on the tissues, novel clinically effective therapeutic strategies targeted to those processes are urgently needed. In this study, to discover a new drug candidate for ATTR amyloidosis therapy, we focused on polyamidoamine dendrimer (dendrimer), a 3D-structural nanomaterial, which has a branched cationic polymer repeating polyamidoamine units. Dendrimer (G2) not only inhibited ATTR V30M amyloid fibril formation, but also reduced already formed ATTR V30M amyloid fibrils by reducing β-sheet structure of ATTR V30M protein. Moreover, intravenous administration of dendrimer (G2) reduced TTR deposition in human ATTR V30M transgenic rats. These results indicate that dendrimer (G2) may possess both inhibitory and breaking effects on ATTR V30M amyloid, suggesting that dendrimer has the potential as a dual effective agents against TTR amyloidosis.