Characterization of macrocyclic peptide drug interactions with bile salts and biorelevant colloids via single amino acid mutations and 1H nuclear magnetic resonance (NMR) spectroscopy.

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Journal of pharmaceutical sciences Pub Date : 2024-10-24 DOI:10.1016/j.xphs.2024.10.021
Tahnee J Dening, José G Napolitano, Jessica L Ochoa, Justin T Douglas, Michael J Hageman
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Abstract

There is growing interest in the oral delivery of poorly permeable peptide drugs; however, the effect of biorelevant colloids found in the aqueous gastrointestinal environment on peptide drug solution behavior has been largely understudied. In this work, we detail the molecular level interactions between octreotide, a water-soluble macrocyclic peptide drug, and biorelevant colloids, i.e. bile salt micelles and bile salt-phospholipid mixed micelles, via dialysis membrane flux experiments and proton nuclear magnetic resonance (1H NMR) spectroscopy. A modified alanine scan was employed to generate eight mutated octreotide analogs; the impact of individual amino acid mutations on peptide dialysis membrane flux rates in micellar (trihydroxy and dihydroxy) bile salt solutions as well as fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) was evaluated and compared against the parent peptide, octreotide. We show that octreotide interacts more strongly with dihydroxy bile salt micelles than trihydroxy bile salt micelles in solution, and in FaSSIF/FeSSIF media, octreotide mainly interacts with the phospholipid component. These interactions are largely mediated by hydrophobic interactions of octreotide's aromatic residues as well as electrostatic interactions between octreotide's basic Lys residue and terminal amine.

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通过单氨基酸突变和 1H 核磁共振 (NMR) 光谱鉴定大环肽药物与胆汁盐和生物相关胶体的相互作用。
人们对渗透性差的多肽药物的口服给药越来越感兴趣;然而,胃肠道水环境中的生物相关胶体对多肽药物溶液行为的影响在很大程度上还没有得到充分研究。在这项工作中,我们通过透析膜通量实验和质子核磁共振(1H NMR)光谱详细研究了水溶性大环肽药物奥曲肽与生物相关胶体(即胆汁盐胶束和胆汁盐-磷脂混合胶束)之间的分子水平相互作用。我们采用改良丙氨酸扫描法生成了八种突变的奥曲肽类似物;评估了单个氨基酸突变对胶束(三羟基和二羟基)胆汁盐溶液以及空腹状态模拟肠液(FaSSIF)和进食状态模拟肠液(FeSSIF)中肽透析膜通量率的影响,并与母肽奥曲肽进行了比较。我们的研究表明,在溶液中,奥曲肽与二羟基胆盐胶束的相互作用比与三羟基胆盐胶束的相互作用更强;在 FaSSIF/FeSSIF 介质中,奥曲肽主要与磷脂成分相互作用。这些相互作用主要是由奥曲肽芳香族残基的疏水作用以及奥曲肽碱性赖氨酸残基和末端胺之间的静电作用介导的。
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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.
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