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具有内部可离子化非天然氨基酸的自组装肽:一种 pH 响应性肽材料的通用方法。

Self-assembling Peptides with Internal Ionizable Unnatural Amino Acids: A General Approach to pH-responsive Peptide Materials.

机构信息

Department of Chemistry and Biochemistry, The University of Texas at Arlington, 701 S Nedderman Dr, Arlington, 76019 TX, USA.

Department of Bioengineering, The University of Texas at Arlington, 701 S Nedderman Dr, 76019 TX, Arlington, USA.

出版信息

Chem Asian J. 2022 Oct 4;17(19):e202200724. doi: 10.1002/asia.202200724. Epub 2022 Sep 1.

Abstract

Self-assembled peptides are an emerging family of biomaterials that show great promise for a range of biomedical and biotechnological applications. Introducing and tuning the pH-responsiveness of the assembly is highly desirable for improving their biological activities. Inspired by proteins with internal ionizable residues, we report a simple but effective approach to constructing pH-responsive peptide assembly containing unnatural ionic amino acids with an aliphatic tertiary amine side chain. Through a combined experimental and computational investigation, we demonstrate that these residues can be accommodated and stabilized within the internal hydrophobic compartment of the peptide assembly. The hydrophobic microenvironment shifts their pK significantly from a basic pH typically found for free amines to a more biologically relevant pH in the weakly acidic range. The pH-induced ionization and ionization-dependent self-assembly and disassembly are thoroughly investigated and correlated with the biological activity of the assembly. This new approach has unique advantages in tuning the pH-responsiveness of self-assembled peptides across a large pH range in a complex biological environment. We anticipate the ionizable amino acids developed here can be widely applicable to the synthesis and self-assembly of many amphiphilic peptides with endowed pH-responsive properties to enhance their biological activities toward applications ranging from targeted therapeutic delivery to proton transport.

摘要

自组装肽是一类新兴的生物材料,它们在生物医学和生物技术的多个领域都具有广阔的应用前景。引入和调节组装体的 pH 响应性,对于提高其生物活性非常重要。受具有内部可离子化残基的蛋白质的启发,我们报告了一种简单而有效的方法,用于构建含有非天然离子氨基酸和脂肪族叔胺侧链的 pH 响应性肽组装体。通过结合实验和计算研究,我们证明这些残基可以被容纳和稳定在肽组装体的内部疏水区内。疏水环境使这些残基的 pK 值从通常在游离胺中发现的碱性 pH 值显著移动到更接近弱酸性范围内的生物学相关 pH 值。我们彻底研究了 pH 诱导的离解以及离解依赖性的自组装和自解组装,并将其与组装体的生物活性相关联。这种新方法在复杂的生物环境中,在很大的 pH 范围内调节自组装肽的 pH 响应性方面具有独特的优势。我们预计这里开发的可离子化氨基酸可以广泛应用于许多两亲性肽的合成和自组装,赋予它们 pH 响应性,以提高其在从靶向治疗药物输送到质子传输等应用中的生物活性。

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