在Gramicidin S中进行β-Turn编辑:活动对用立体动态气取代proline α-carbon的影响
Jhajan Lal1, Grace Kaul2, Abdul Akhir3
1Division of Medicinal and Process Chemistry, CSIR-CDRI, Lucknow 226031, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, UP 201002, India.
Bioorganic chemistry
|June 10, 2023
概括
通过编辑proline来修改天然抗微生物Gramicidin S,降低了其对红细胞 (RBC) 的毒性,并保持了其对细菌感染的有效性. 这表明了更安全的局部抗生素应用的潜力.
科学领域:
- 生物化学 生物化学
- 药用化学 医学化学
- 微生物学 微生物学
背景情况:
- 格拉米西丁S是一种天然的抗微生物,用于药片中,但受到红细胞 (RBC) 细胞毒性限制.
- 开发具有降低毒性的新型抗生素对于临床应用至关重要.
研究的目的:
- 为了研究用立体动力编辑烯α-碳对Gramicidin S的生物活性和细胞毒性的影响.
- 为了比较修改后的格拉米西丁S类别与天然的疗效和安全性.
主要方法:
- 使用固相合成合成天然Gramicidin S,proline编辑和野生类型β-turn模仿剂.
- 对抗临床相关细菌病原体的抗微生物活性评估 (例如大肠杆菌,肺炎菌,黄金菌,杆菌). ) 的情况.
- 对VERO细胞和红细胞的细胞毒性评估.
主要成果:
- 一种单氨酸编辑模拟物 (13),对抗大肠杆菌和肺炎菌的抗菌活性有中等改善.
- 13对抗多药耐药性 (MDR) 黄金色细菌和菌种类 (Enterococcus spp.) 显示出具有同效的抗微生物作用.
- 与Gramicidin S.相比,proline编辑的具有两到五倍低的细胞毒性.
结论:
- 在格拉米西丁S中引入单个azPro/Pro突变,会略微增强抗菌活性.
- 修改后的具有显著降低的细胞毒性,这表明改善局部抗生素治疗的潜力.
相关概念视频
01:13meta-Directing Deactivators: –NO2, –CN, –CHO, –CO2R, –COR, –CO2H
5.6K
All meta-directing substituents are deactivating groups. These substituents withdraw electrons from the aromatic ring, making the ring less reactive toward electrophilic substitution. For example, the nitration of nitrobenzene is 100,000 times slower than that of benzene because of the deactivating effect of the nitro group. The first step in an electrophilic aromatic substitution is the addition of an electrophile to form a resonance-stabilized carbocation. The energy diagrams for...
5.6K
00:49Ligand Binding and Linkage
4.8K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.8K
01:19Allosteric Proteins-ATCase
5.8K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.8K
01:18Directing and Steric Effects in Disubstituted Benzene Derivatives
3.1K
When disubstituted benzenes undergo electrophilic substitution, the product distribution depends on the directing effect of both substituents. When the directing effects of both substituents reinforce each other, a single product is obtained. For example, bromination of p-nitrotoluene occurs ortho to the methyl group and meta to the nitro group, which is the same position, resulting in a single product. However, if the directing effects of the two groups oppose each other, the...
3.1K
01:11ortho–para-Directing Activators: –CH3, –OH, –NH2, –OCH3
6.1K
All ortho–para directors, excluding halogens, are activating groups. These groups donate electrons to the ring, making the ring carbons electron-rich. Consequently, the reactivity of the aromatic ring towards electrophilic substitution increases. For instance, the nitration of anisole is about 10,000 times faster than the nitration of benzene. The electron-donating effect of the methoxy group in anisole activates the ortho and para positions on the ring and stabilizes the corresponding...
6.1K