Electrostatic control of bioactivity.
Electrostatic control of bioactivity.
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DOI：
10.1002/anie.201100202
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发表时间：
2011-07-04
影响因子：
16.6
通讯作者：
Stupp, Samuel I.
中科院分区：
文献类型：
--
作者：
Goldberger, Joshua E.;Berns, Eric J.;Bitton, Ronit;Newcomb, Christina J.;Stupp, Samuel I.
了解如何设计人工细胞外基质，有效地发出信号并指导细胞反应，对于创造再生医学的新疗法至关重要可注射的、自组装的生物材料能够在细胞周围原位形成支架，因为它们的微创输送是有希望的治疗候选者。[1c， 2]自组装生物活性结构的信号传导作用不仅取决于分子结构，还取决于纳米尺度的形态。[1b， 3]肽两亲体（Peptide amphiphiles, PAs; Scheme 1）是一类可以自发自组装成各种纳米结构的分子，包括球形胶束、纤维和带状，并显示出很好的治疗功能。[1c， 4]人们发现纤维具有特别的生物活性。形成纤维的PA分子通常由四个主要部分组成：1)疏水性基团，通常是烷基尾，通过疏水性坍塌驱动聚集；2)促进纳米纤维形成的β-薄片形成肽；3)含有可电离侧链残基的肽段；4)设计用于与细胞受体相互作用的信号片段。这些分子自组装成高纵横比的纳米纤维，当离子侧链上的电荷被适当地筛选后，在低浓度的水中形成凝胶。这些圆柱形纳米纤维在接近范德华密度时显示出垂直于其长轴的生物活性序列我们已经证明含有层粘胶蛋白衍生的五肽IKVAV的PAs可以诱导神经干细胞向神经元分化，促进神经突生长，并导致急性脊髓损伤后功能改善。[5,6]因此，含有该表位的结构也可能对需要新神经元的再生治疗产生深远影响，如帕金森病和阿尔茨海默病，并有助于创伤或中风后的脑组织修复。IKVAV表位已被证明与至少两种受体结合，即110 kDa的层粘连蛋白结合蛋白（LBP110/APP）和核蛋白[7]，尽管这种结合的确切分子排列和信号转导途径尚未阐明。这种IKVAV五聚体主要含有疏水残基的氨基酸，这些氨基酸具有很强的β-sheet倾向，而含有该表位的肽具有很强的形成淀粉样原纤维的倾向如果这个IKVAV片段与邻近的表位以刚性β-sheet构象存在，那么它与目标受体结合的能力将受到高度限制。事实上，在之前的研究中，IKVAV共价移植到聚合物支架上，并没有观察到神经突生长和神经元分化的增强，[10]可能是由于无效的表位呈递。因此，需要一种有效的超分子策略来控制这种和其他疏水生物活性信号的表位呈现，以增强生物材料的信号转导。我们在此报告了一种利用静电来控制含有疏水IKVAV表位的PA分子的组装行为的设计策略。本研究的PAs含有一个棕榈酸尾部，一个VVAA β-片状区，不同数量的带电谷氨酸残基和甘氨酸残基，以及IKVAV （Scheme1）。设计的关键要素是增加IKVAV片段之前的带电氨基酸残基的数量，以减少表位聚集的倾向。采用固相Fmoc法合成PAs （Fmoc= 9-芴基甲氧基-）
Understanding of how to design artificial extracellular matrices that effectively signal and direct cellular responses is essential for the creation of new therapies in regenerative medicine.[1] Injectable, self-assembling biomaterials capable of forming scaffolds in situ around cells are promising therapeutic candidates because of their minimally invasive delivery.[1c, 2] The signaling efficacy of self-assembling bioactive structures will depend not only on molecular structure but also on nanoscale morphology.[1b, 3] Peptide amphiphiles (PAs; Scheme 1) are a class of molecules that spontaneously self-assemble into a variety of nanostructures, including spherical micelles, fibers, and ribbons, and have shown promising therapeutic functions.[1c, 4] Fibers have been found to be particularly bioactive. PA molecules that form fibers consist typically of four main segments: 1) a hydrophobic group, commonly an alkyl tail, that drives aggregation through hydrophobic collapse; 2) a β-sheet-forming peptide that promotes nanofiber formation; 3) a peptide segment that contains ionizable side-chain residues; and 4) a signaling moiety designed to interact with cellular receptors. These molecules self-assemble into high-aspect-ratio nanofibers that form gels in water at low concentrations when the charges on the ionic side chains are appropriately screened. These cylindrical nanofibers display bioactive sequences perpendicular to their long axis at near van der Waals density.[5] We have shown that PAs containing the laminin-derived pentapeptide IKVAV can induce differentiation of neural stem cells into neurons, promote neurite outgrowth, and lead to functional improvement after acute spinal-cord injury.[5, 6] Therefore, structures containing this epitope could also have a profound impact on regenerative therapies requiring new neurons, such as Parkinson s and Alzheimer s disease, and also help to repair brain tissue following trauma or stroke. The IKVAV epitope has been shown to bind to at least two receptors, a 110 kDa laminin-binding protein (LBP110/APP) and nucleolin,[7] although the exact molecular arrangement of this binding and the signal-transduction pathways have yet to be elucidated. This IKVAV pentamer contains mostly amino acids with hydrophobic residues that have a strong β-sheet propensity,[8] and peptides containing this epitope have a strong tendency to form amyloid-like fibrils.[9] If this IKVAV segment were to exist in a rigid β-sheet conformation with neighboring epitopes, its ability to bind to the target receptor would be highly restricted. In fact, in previous studies on IKVAV covalently grafted to polymer scaffolds, enhanced neurite outgrowth and neuronal differentiation were not observed,[10] possibly as a result of ineffective epitope presentation. Consequently, an effective supramolecular strategy to control the epitope presentation of this and other hydrophobic bioactive signals is required to enhance the signal transduction of biomaterials. We report herein a design strategy that utilizes electrostatics to control the assembly behavior of PA molecules containing the hydrophobic IKVAV epitope. The PAs in this study contain a palmitic acid tail, a VVAA β-sheet-forming region, different numbers of charged glutamic acid residues and glycine residues, and IKVAV (Scheme1). The key element of the design is the increased number of charged amino acid residues preceding the IKVAV segment, to reduce the propensity for epitope aggregation. PAs were synthesized by solid-phase Fmoc synthesis (Fmoc= 9-fluorenylmethoxy-
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DOI：
10.1073/pnas.90.21.10150
发表时间：
1993-11-01
影响因子：
11.1
作者：
KIBBEY, MC;JUCKER, M;KLEINMAN, HK
通讯作者：
KLEINMAN, HK
影响因子：
15
作者：
Yu, YC;Berndt, P;Fields, GB
通讯作者：
Fields, GB
影响因子：
2.9
作者：
LEVITT, M
通讯作者：
LEVITT, M
影响因子：
56.9
作者：
Hartgerink, JD;Beniash, E;Stupp, SI
通讯作者：
Stupp, SI
影响因子：
5.3
作者：
Tysseling-Mattiace, Vicki M.;Sahni, Vibhu;Kessler, John A.
通讯作者：
Kessler, John A.