循环的肠道透性:发现了常见的关键骨干动机
Johannes G Beck1, Jayanta Chatterjee, Burkhardt Laufer
1Institute for Advanced Study and Center for Integrated Protein Science at the Technische Universität München, Department Chemie, Lichtenbergstrasse 4, 85747 Garching, Germany.
Journal of the American Chemical Society
|June 29, 2012
概括
研究人员确定了两个具有高Caco-2细胞透性的结构. N-甲基化模式是实现这些治疗药物的口服生物可用性的关键.
科学领域:
- 酸化学和药物发现.
- 结构生物学和生物物理学.
- 药理动力学和药物输送.
背景情况:
- 类治疗药物面临着口服生物利用性的挑战,限制了它们的临床使用.
- 现有的小分子生物可用性规则不适用于.
- 了解体结构-透性关系对于开发口服体药物至关重要.
研究的目的:
- 识别和描述高 Caco-2 透性结构.
- 研究N-甲基化模式在的口服生物利用性中的作用.
- 探索这些结构作为口服生物可用类候选药物的模板的潜力.
主要方法:
- 合成和选的图书馆54个循环-D-ala-ala-ala-5) - - 具有不同的N-甲基化.
- 卡科-2细胞透性测试用于评估药物吸收潜力.
- 结构分析以确定关键的结构特征 (例如,β转,cis键).
主要成果:
- 确定了两个不同的,高度透的Caco-2样结构.
- 全转化模板需要在D-Ala(1) 和Ala(6) 处进行特定的N-甲基化,以获得高透性.
- 单一cis模板,在Ala(5) 之前具有cis键,只有当D-Ala(1) 被N-甲基化时,才显示出高透性.
结论:
- 特定的N-甲基化模式对于在已识别的模板中实现高Caco-2透性至关重要.
- 这些已识别的结构与已知的口服生物可用,如索马托斯塔丁类同类和环素A具有相似之处.
- 这些Caco-2透模板为开发新型口服生物可用疗法提供了有前途的战略.
相关概念视频
01:32Lipids as Anchors
In the plasma membrane, the lipids forming the bilayer can also act as an anchor to tether proteins to the membrane. The three main types of lipid anchors found in eukaryotes are – prenyl groups, fatty acyl groups, and glycosylphosphatidylinositol or GPI groups. Prenyl and fatty acyl groups act as anchors on the cytosolic surface of the membrane, whereas GPI anchors proteins on the extracellular side.
The carboxy-terminal of most of the prenylated proteins, such as Ras proteins, contains the...
The carboxy-terminal of most of the prenylated proteins, such as Ras proteins, contains the...
01:28Peptidoglycan Synthesis
Structure of PeptidoglycanPeptidoglycan is a vital structural component of the bacterial cell wall, providing mechanical strength and shape to the cell. It consists of repeating units of two sugars—N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM)—linked by β-1,4 glycosidic bonds. These sugar chains are cross-linked by short peptide chains, forming a mesh-like polymer that surrounds the bacterial plasma membrane.Cytoplasmic Phase – Precursor SynthesisPeptidoglycan biosynthesis begins in...
02:43Peptide Bonds
A peptide bond covalently attaches amino acids through a dehydration reaction. One amino acid's carboxyl group and another amino acid's amino group combine, releasing a water molecule. The resulting bond is the peptide bond. The products that such linkages form are peptides. As more amino acids join this growing chain, the resulting chain is a polypeptide. Each polypeptide has a free amino group at one end. This end has the N-terminal, or the amino-terminal, and the other end has a free...
01:09Multi-pass Transmembrane Proteins and β-barrels
In multi-pass transmembrane proteins, the polypeptide chain crosses the membrane more than once. The transmembrane polypeptide chain either forms an α-helix or β-strand structure. α-Helix containing multi-pass transmembrane proteins are ubiquitous, whereas β-strand containing ones are mainly found in gram-negative bacteria, mitochondria, and chloroplasts.
α-Helix containing multi-pass transmembrane proteins
Multi-pass transmembrane proteins such as G-protein-linked receptors (GPCRs) and...
α-Helix containing multi-pass transmembrane proteins
Multi-pass transmembrane proteins such as G-protein-linked receptors (GPCRs) and...
01:29GPI Anchoring of Proteins in the ER Membrane
GPI-anchoring is a post-translational, reversible protein modification that is ubiquitous in eukaryotes. Such proteins are primarily present on the exoplasmic leaflet of the plasma membrane.
GPI-anchor structure
A sequence of 11 enzymatic reactions results in the synthesis of the complete GPI anchor consisting of a hydrophobic and a hydrophilic portion. The hydrophobic portion comprises phosphatidylinositol, while the hydrophilic part comprises polar groups like phosphoethanolamine,...
GPI-anchor structure
A sequence of 11 enzymatic reactions results in the synthesis of the complete GPI anchor consisting of a hydrophobic and a hydrophilic portion. The hydrophobic portion comprises phosphatidylinositol, while the hydrophilic part comprises polar groups like phosphoethanolamine,...
01:27Bioavailability Enhancement: Drug Permeability Enhancement
After oral administration, poor permeability often limits the rate at which drugs are absorbed through the intestinal epithelium. Enhancing drug permeability is crucial for effective therapy, and several strategies have been developed to overcome this challenge.One effective strategy involves the use of lipid-based formulations. These formulations enhance dissolution and solubility, targeting physiological mechanisms to increase drug absorption. This includes stimulating bile salt secretion,...