Self-assembly Stability Compromises the Efficacy of Tryptophan-Containing Designed Anti-measles Virus Peptides
Self-assembly Stability Compromises the Efficacy of Tryptophan-Containing Designed Anti-measles Virus Peptides
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自组装稳定性损害了含色氨酸设计的抗麻疹病毒肽的功效
DOI：
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
E. Martínez
中科院分区：
文献类型：
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作者：
E. Martínez
麻疹等几种传染病的死灰复燃推动了人们寻找新的化疗药物来预防和治疗病毒感染。自组装抗病毒肽是一类有前途的进入抑制剂，能够满足这一需求。源自麻疹融合蛋白 C 端 (HRC) 七肽重复序列、二聚化并与亲脂基团缀合的融合抑制肽被发现对麻疹病毒有效。由这些肽形成的自组装纳米颗粒的结构调节它们的活性。基于对天然麻疹病毒分离株融合蛋白中 L454W 突变的分析，合成了在 454 位带有色氨酸残基的 HRC 肽 (HRC-L454W)，目的是改善膜锚定和操纵自组装。单体和二聚肽，无论是否与单个亲脂基团缀合，都能减少体内感染。相反，与亲脂基团的双缀合会消除活性。基于HRC-L454W肽的物理化学性质、自组装和膜插入动力学，我们表明双共轭增加了自发自组装纳米颗粒内核的稳定性和有序性，从而导致其压实。色氨酸残基的存在也增加了二聚肽纳米颗粒中的空间位阻效应，有助于肽间簇的啮合，但未达到相同水平的压缩。我们提出，形成自组装纳米颗粒内核的分子簇的高度有序堆积和稳定性阻止了肽在体内的有效解离，阻碍了它们的释放，从而消除了它们的抗病毒功效。
The resurgence of several infectious diseases, like measles, has driven the search for new chemotherapeutics to prevent and treat viral infections. Self-assembling antiviral peptides are a promising class of entry inhibitors capable of meeting this need. Fusion inhibitory peptides derived from the heptad repeat of the C-terminal (HRC) of the measles fusion protein, dimerized and conjugated with lipophilic groups, were found to be efficacious against measles virus. The structures of the self-assembled nanoparticles formed by these peptides modulated their activity. Based on the analysis of a L454W mutation in the fusion protein of a naturally occurring measles viral isolate, HRC peptides bearing the tryptophan residue at position 454 (HRC-L454W) were synthesized with the goal of improving membrane anchoring and manipulating self-assembly. Monomeric and dimeric peptides, whether conjugated or not to a single lipophilic group, reduced infection in vivo. Bis-conjugation with lipophilic groups, in contrast, abrogated activity. Based on the physicochemical properties, self-assembly and membrane insertion kinetics of the HRC-L454W peptides we show that bis-conjugation increases the stability and order of the inner core of the spontaneously self-assembled nanoparticles, resulting in their compaction. The presence of the tryptophan residue also increases steric hindrance effects in the nanoparticle of the dimeric peptides, contributing to inter-peptide cluster meshing, but the same level of compaction is not achieved. We propose that the highly ordered packing and stability of molecular clusters forming the inner core of self-assembled nanoparticles prevent efficient dissociation of the peptides in vivo, hindering their release and therefore eliminating their antiviral efficacy.
DOI：
10.1073/pnas.89.10.4462
发表时间：
1992-05-15
影响因子：
11.1
作者：
ZHONG, LX;JOHNSON, WC
通讯作者：
JOHNSON, WC
影响因子：
5.4
作者：
Karmali, Priya Prakash;Kotamraju, Venkata Ramana;Kastantin, Mark;Black, Matthew;Missirlis, Dimitris;Tirrell, Matthew;Ruoslahti, Erkki
通讯作者：
Ruoslahti, Erkki
影响因子：
41.2
作者：
通讯作者：
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