Synthetic alpha-helix mimetics as agonists and antagonists of islet amyloid polypeptide aggregation.
Synthetic alpha-helix mimetics as agonists and antagonists of islet amyloid polypeptide aggregation.
复制标题
DOI：
10.1002/anie.200901694
复制
发表时间：
2010
影响因子：
16.6
通讯作者：
Hamilton, Andrew D.
中科院分区：
文献类型：
--
作者：
Saraogi, Ishu;Hebda, James A.;Becerril, Jorge;Estroff, Lara A.;Miranker, Andrew D.;Hamilton, Andrew D.
开发能够调节蛋白质聚集过程的破坏性作用的小分子仍然是当代药物化学的一个高度优先目标。[1]这些聚集体中的一个重要类别，称为淀粉样蛋白，与许多退行性疾病有关，包括阿尔茨海默病、II型糖尿病、老年系统性淀粉样变性（SSA）、朊病毒疾病和类风湿性关节炎。这些与病理学无关的疾病共有的属性是正常可溶性蛋白质经历构象变化，导致自组装成细胞毒性形式，最终形成富含β折叠的纤维状结构。胰岛淀粉样多肽（IAPP）或胰淀素是一种与II型糖尿病淀粉样蛋白生成有关的蛋白质。[2]IAPP由胰岛β细胞与胰岛素共同分泌，并且认为IAPP的聚集形式在II型糖尿病病理学中的β细胞毒性中起作用。[3]淀粉样蛋白形成过程通过依赖成核的反应机制进行。然而，成核的结构和能量基础却知之甚少。[5]对于IAPP，Miranker及其同事[6]提出了一种可能的机制，其中通过残基1-20介导的接触将IAPP结合到细胞膜上来启动成核
The development of small molecules that can modulate the damaging effects of protein aggregation processes remains a high priority goal in contemporary medicinal chemistry.[1] An important class of these aggregates, called amyloids, has been implicated in numerous degenerative diseases including Alzheimer’s, type II diabetes, senile systemic amyloidosis (SSA), prion diseases and rheumatoid arthritis. The attribute shared by these symptomatically unrelated diseases is that a normally soluble protein undergoes a conformational change resulting in self-assembly into cytotoxic forms culminating in a βsheet rich fibrillar structure. Islet amyloid polypeptide (IAPP), or amylin, is one such protein that has been implicated in amyloidogenesis in type II diabetes.[2] IAPP is cosecreted with insulin by the β-cells of the islets of Langerhans and an aggregated form of IAPP is believed to play a role in β-cell toxicity in the pathology of type II diabetes.[3]Amyloid forming processes proceed via a nucleation dependent reaction mechanism. The structural and energetic basis for nucleation is, however, poorly understood.[5] For IAPP, Miranker and coworkers [6] have proposed a possible mechanism where nucleation is initiated by binding of IAPP to cell membranes via contacts mediated by residues 1-20
登录
查看更多内容
影响因子：
2.9
作者：
Jayasinghe, SA;Langen, R
通讯作者：
Langen, R
影响因子：
1.8
作者：
Ahn, Jung-Mo;Han, Sun-Young
通讯作者：
Han, Sun-Young
影响因子：
--
作者：
Hebda JA;Saraogi I;Magzoub M;Hamilton AD;Miranker AD
通讯作者：
Miranker AD
影响因子：
2.9
作者：
Porat, Y;Mazor, Y;Gazit, E
通讯作者：
Gazit, E
影响因子：
2.9
作者：
Knight, Jefferson D.;Hebda, James A.;Miranker, Andrew D.
通讯作者：
Miranker, Andrew D.