β-环糊精衍生物结合环肽兰瑞奥肽的芳香族侧链

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Journal of pharmaceutical sciences Pub Date : 2024-11-02 DOI:10.1016/j.xphs.2024.10.042
Negar Jafari, Justin T Douglas, Sarah A Neuenswander, Payam Kelich, Michael J Hageman
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引用次数: 0

摘要

环糊精复合物具有调节多肽药物理化性质的潜力。肽形成包合物的能力受多种因素的影响,如肽的大小、氨基酸序列以及环糊精空腔的大小和电荷。本研究考察了环肽药物醋酸兰瑞奥肽与两种常见的β-环糊精衍生物--磺丁醚β-CD(SBEβ-CD)和羟丙基β-CD(HPβ-CD)的包合复合物。核磁共振光谱用于研究β-环糊精衍生物与兰瑞奥肽特定残基之间的相互作用。结果表明,兰瑞奥肽序列中芳香残基的疏水侧链可与两种 β-环糊精衍生物的空腔相匹配。此外,核磁共振显示,复合物的扩散系数较低,流体力学半径较大,表明与空腔结合。通过取代兰瑞奥肽中的丙氨酸,对每个芳香族残基进行了单独研究,以测量其与β-环糊精衍生物的结合情况。丙氨酸替代物研究表明,与 HPβ-CD 相比,SBEβ-CD 与兰瑞奥肽的结合力更强。对接研究表明,由于立体阻碍和尺寸因素,1:1 包合复合物比高阶复合物更有利。对接分析表明,所有三个芳香族侧链都与β-环糊精衍生物 SBEβ-CD 和 HPβ-CD 形成了稳定的构象。
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β-Cyclodextrin Derivatives Bind Aromatic Side Chains of the Cyclic Peptide Lanreotide.

Cyclodextrin complexation has a potential to modulate the physicochemical properties of peptide drugs. The ability of peptides to form an inclusion complex can be influenced by factors such as size, amino acid sequence of peptide and the size and charge of the cyclodextrin cavity. In this study, the inclusion complexes of cyclic peptide drug lanreotide acetate with two common β-cyclodextrin derivatives, Sulfobutyl ether β-CD (SBEβ-CD) and hydroxypropyl β-CD (HPβ-CD) were investigated. NMR spectroscopy was used to examine the interaction between β-cyclodextrin derivatives and specific residues of lanreotide. It was observed that the hydrophobic side chain of aromatic residues in the lanreotide sequence can be fit into the cavity of both β-cyclodextrin derivatives. Additionally, NMR revealed a lower diffusion coefficient and higher hydrodynamic radius of complex, indicative of binding to the cavities. Each aromatic residue was individually studied by substituting alanine in lanreotide to measure its association binding with both β-cyclodextrin derivatives. The alanine-substitute study indicated a stronger binding of SBEβ-CD to Lanreotide compared to HPβ-CD. Docking studies suggested that the 1:1 inclusion complex is more favorable than higher order complexes due to the steric hindrance and size considerations. The docking analysis indicated the stable conformation of all three aromatic side chains with both β-cyclodextrin derivatives, SBEβ-CDand HPβ-CD.

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来源期刊
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
期刊介绍: The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.
期刊最新文献
A Survey of Solid Form Landscape: Trends in Occurrence and Distribution of Various Solid Forms and Challenges in Solid Form Selection. Impact of Surfactants on Solution Behavior and Membrane Transport of Amorphous Solid Dispersions. Insights into pharmaceutical co-crystallization using coherent Raman microscopy. β-Cyclodextrin Derivatives Bind Aromatic Side Chains of the Cyclic Peptide Lanreotide. Bioavailability Improvement by Atomic Layer Coating: Fenofibrate A Case Study.
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