Department of Chemistry, Laboratory for Organic Synthesis of Functional Systems, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489, Berlin, Germany.
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Sigmund-Freud-Str. 27, 53127 Bonn, Forschungszentrum CAESAR, Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
Macromol Biosci. 2017 Oct;17(10). doi: 10.1002/mabi.201700109. Epub 2017 May 10.
The pharmacological profiles of small molecule drugs are often challenged by their poor water solubility. Sequence-defined peptides attached to poly(ethylene glycol) (PEG) offer opportunities to overcome these difficulties by acting as drug-specific formulation additives. The peptide-PEG conjugates enable specific, noncovalent drug binding via tailored peptide/drug interactions as well as provide water solubility and drug shielding by well-solvated PEG-blocks. A systematic set of specific solubilizers for B4A1 as a potential anti-Alzheimer disease drug is synthesized and variations involve the length of the PEG-blocks as well as the sequences of the peptidic drug-binding domain. The solubilizer/B4A1 complexes are studied in order to understand contributions of both PEG and peptide segments on drug payload capacities, drug/carrier aggregate sizes, and influences on inhibition of the Tau-protein aggregation in an in vitro assay.
小分子药物的药理学特性常常受到其较差水溶性的限制。通过将序列定义的肽连接到聚乙二醇（PEG）上，可以作为药物特异性制剂添加剂来克服这些困难。肽-PEG 缀合物通过定制的肽/药物相互作用实现特定的非共价药物结合，同时通过良好溶剂化的 PEG 链段提供水溶性和药物屏蔽作用。为了将 B4A1 作为一种有潜力的抗阿尔茨海默病药物进行开发，我们合成了一系列特定的 B4A1 增溶剂，并对其进行了各种修饰，包括 PEG 链段的长度和肽类药物结合域的序列。我们对增溶剂/B4A1 复合物进行了研究，以了解 PEG 和肽段对药物有效载药量、药物/载体聚集物大小的贡献，以及对体外试验中 Tau 蛋白聚集抑制的影响。
