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Polyvalent Hybrid Virus-Like Nanoparticles with Displayed Heparin Antagonist Peptides
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-06-14 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00135
Justin M. Choi 1 , Valerie Bourassa 1 , Kevin Hong 1 , Michael Shoga 1 , Elizabeth Y. Lim 1 , Andrew Park 1 , Kazim Apaydin 1 , Andrew K. Udit 1
Affiliation  

The potential applications for nanomaterials continue to grow as new materials are developed and environmental and safety concerns are more adequately addressed. In particular, virus-like particles (VLPs) have myriad applications in medicine and biology, exploiting both the reliable, symmetric self-assembly mechanism and the ability to take advantage of surface functionalities that may be appropriately modified through mutation or bioconjugation. Herein we describe the design and application of hybrid VLPs for use as potent heparin antagonists, providing an alternative to the toxic heparin antidote protamine. A two-plasmid system was utilized to generate VLPs that contain both the wild-type coat protein and a second coat protein with either a C- or N-terminal cationic peptide extension (4–28 amino acids). Incorporation of the modified coat proteins varied from 8 to 31%, while activated partial thromboplastin time (APTT) assays revealed a range of the heparin antagonist activity. Notably, when examined on the basis of the quantity of peptide delivered due to the varied incorporation rates, it appeared that the VLPs largely followed a similar trend, with the quantity of peptide delivered more closely correlating with heparin antagonist activity. The particle with the highest incorporation rate and best antiheparin activity displayed the C-terminal peptide ARK2A2KA, which corresponds to the Cardin–Weintraub consensus sequence for binding to glycosaminoglycans. Analysis of this particle using heparin affinity chromatography with fraction collection revealed that particles eluting at higher salt concentration had a greater proportion of peptide incorporation. Preliminary dual polarization interferometry experiments further support a strong interaction between this particle and heparin.

中文翻译:

具有展示肝素拮抗剂肽的多价杂合病毒样纳米颗粒。

随着新材料的开发以及对环境和安全问题的更充分解决,纳米材料的潜在应用继续增长。尤其是,病毒样颗粒(VLP)在医学和生物学中有着无数的应用,既利用了可靠的,对称的自组装机制,又利用了可以通过突变或生物缀合进行适当修饰的表面功能的能力。本文中,我们描述了用作有效肝素拮抗剂的杂合VLP的设计和应用,为有毒的肝素解毒剂鱼精蛋白提供了替代品。利用两质粒系统生成VLP,该VLP既包含野生型外壳蛋白,又包含具有C或N端阳离子肽延伸(4–28个氨基酸)的第二外壳蛋白。修饰的外壳蛋白的掺入率在8%到31%之间,而活化的部分凝血活酶时间(APTT)分析显示了一系列肝素拮抗剂活性。值得注意的是,当基于因掺入速率变化而递送的肽的量进行检查时,似乎VLP在很大程度上遵循相似的趋势,其中递送的肽的量与肝素拮抗剂活性更紧密相关。具有最高掺入率和最佳抗肝素活性的颗粒显示出C端肽ARK 似乎VLP基本上遵循相似的趋势,所输送的肽量与肝素拮抗剂的活性更紧密相关。具有最高掺入率和最佳抗肝素活性的颗粒显示出C端肽ARK 似乎VLP基本上遵循相似的趋势,所输送的肽量与肝素拮抗剂的活性更紧密相关。具有最高掺入率和最佳抗肝素活性的颗粒显示出C端肽ARK2 A 2 KA,对应于与糖胺聚糖结合的Cardin–Weintraub共有序列。使用肝素亲和色谱法和级分收集对该颗粒进行分析,结果表明,以较高盐浓度洗脱的颗粒具有更大比例的肽结合。初步的双极化干涉测量实验进一步支持了该颗粒与肝素之间的强相互作用。
更新日期:2018-06-14
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