Peptide Conjugates of Benzene Carboxylic Acids as Agonists and Antagonists of Amylin Aggregation.
Peptide Conjugates of Benzene Carboxylic Acids as Agonists and Antagonists of Amylin Aggregation.
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DOI：
10.1021/acs.bioconjchem.6b00732
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发表时间：
2017-02-15
影响因子：
4.7
通讯作者：
Desamero RZ
中科院分区：
文献类型：
--
作者：
Profit AA;Vedad J;Desamero RZ
人胰岛淀粉样多肽（hIAPP），也称为胰淀素，是一种 37 残基肽激素，与胰岛素一起储存和共同分泌。 hIAPP 在 2 型糖尿病中发挥着关键作用，是在患有该疾病的患者胰腺中发现的淀粉样蛋白沉积物的主要成分。 hIAPP 的自组装和淀粉样蛋白的形成与产生胰岛素的 β 细胞的死亡有关。最近的研究结果表明，可溶性 hIAPP 寡聚体是导致 β 细胞损失的细胞毒性物质，而淀粉样原纤维本身可能确实是无害的。治疗干预的潜在途径包括开发阻止 hIAPP 自组装的化合物，以及减少或消除滞后时间并快速加速淀粉样原纤维形成的化合物。这两种方法都最大限度地减少了可溶性细胞毒性 hIAPP 寡聚物的暂时暴露。为此，我们的实验室采用静电排斥方法来开发 hIAPP 自组装的潜在抑制剂和调节剂。构建了肽缀合物，其中不同电荷的苯甲酸被用作静电破坏元件，并附加到 hIAPP22-29 (NFGAILSS) 自我识别序列的 N 末端。通过浊度测量来表征缀合物的自组装动力学，并通过拉曼和 CD 光谱探测聚集体的结构，同时使用透射电子显微镜评估形态。几种苯甲酸肽缀合物未能自组装，一些被发现可以抑制全长胰岛淀粉样蛋白的聚集，而另一些则有助于提高淀粉样蛋白的形成速率和/或增加所产生的淀粉样蛋白的产量。研究表明，缀合物苯环上游离羧酸盐的几何展示对缀合物的活性起着重要作用。此外，还发现许多游离苯羧酸能够自行调节胰淀素自组装。这些研究的结果证实了静电排斥方法调节淀粉样蛋白形成的可行性，并可能有助于潜在治疗剂的设计和开发。
Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37 residue peptide hormone that is stored and co-secreted with insulin. hIAPP plays a pivotal role in type 2 diabetes and is the major component of amyloid deposits found in the pancreas of patients afflicted with the disease. The self-assembly of hIAPP and the formation of amyloid is linked to the death of insulin producing β-cells. Recent findings suggest that soluble hIAPP oligomers are the cytotoxic species responsible for β-cell loss whereas amyloid fibrils themselves may indeed be innocuous. Potential avenues of therapeutic intervention include the development of compounds that prevent hIAPP self-assembly as well as those that reduce or eliminate lag time and rapidly accelerate the formation of amyloid fibrils. Both of these approaches minimize temporal exposure to soluble cytotoxic hIAPP oligomers. Toward this end our laboratory has pursued an electrostatic repulsion approach to the development of potential inhibitors and modulators of hIAPP self-assembly. Peptide conjugates were constructed in which benzene carboxylic acids of varying charge were employed as electrostatic disrupting elements and appended to the N-terminal of the hIAPP22–29 (NFGAILSS) self-recognition sequence. The self-assembly kinetics of conjugates were characterized by turbidity measurements and the structure of aggregates probed by Raman and CD spectroscopy while the morphology was assessed using transmission electron microscopy. Several benzene carboxylic acid peptide conjugates failed to self-assemble and some were found to inhibit the aggregation of full-length amylin while others served to enhance the rate of amyloid formation and/or increase the yield of amyloid produced. Studies reveal that the geometric display of free carboxylates on the benzene ring of the conjugates plays an important role in the activity of conjugates. In addition, a number of free benzene carboxylic acids were found to modulate amylin self-assembly on their own. The results of these investigations confirm the viability of the electrostatic repulsion approach to the modulation of amyloid formation and may aid the design and development of potential therapeutic agents.
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影响因子：
4.3
作者：
Akter R;Cao P;Noor H;Ridgway Z;Tu LH;Wang H;Wong AG;Zhang X;Abedini A;Schmidt AM;Raleigh DP
通讯作者：
Raleigh DP
人类 IAPP 中淀粉样蛋白的形成机制：二聚体具有 β 链单体-单体界面。
影响因子：
15
作者：
Dupuis NF;Wu C;Shea JE;Bowers MT
通讯作者：
Bowers MT
影响因子：
4.8
作者：
Jha, Suman;Patil, Sharadrao M.;Alexandrescu, Andrei T.
通讯作者：
Alexandrescu, Andrei T.
影响因子：
6.8
作者：
Mason, JM;Kokkoni, N;Doig, AJ
通讯作者：
Doig, AJ
影响因子：
4.3
作者：
Hassanpour, Avid;De Carufel, Carole Anne;Forgione, Pat
通讯作者：
Forgione, Pat