DEVELOPMENT OF NEW LIPID A BINDING AGENTS
新型脂质A结合剂的开发
基本信息
- 批准号:2608975
- 负责人:
- 金额:$ 16.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-06-01 至 2003-05-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION: Sepsis affects the lives of hundreds of thousands of people
each in the U.S. Sepsis caused by Gram-negative bacteria results from
adverse host immune response to the Lipid A (LA) portion of endotoxin.
Compounds with high affinity for LA, including polymyxin B (PMB) and
derivatives, are capable of detoxifying LA nd protection a host against
sepsis. By binding LA, these compounds also sensitize Gram-negative
bacteria to hydrophobic antibiotics. However, therapeutic use of PMB
is limited due to its toxicity. The aim of this research is to develop
small molecules capable of strong and selective associating with LA for
use in treatment of sepsis and as means of fighting bacterial infection.
Taking the interactions of PMB with LA as a model, this research focuses
on the preparation of simple compounds, based on cholic acid
scaffolding, capable of mimicking the LA-binding behavior of PMB but
lacking the toxicity of the antibiotic. Simple cholic-acid based LA
binders will present many advantages over reported LA binding molecules
including: ease of preparation and derivatization, greater control over
biological stability, and potential oral bioavailablity. Cholic acid
derivatives were designed to mimic a conformation of PMB believed to be
important in its association with LA. Preliminary experiments with
cholic acid derivatives demonstrate their ability to sensitize Gram-
negative bacteria to hydrophobic antibiotics, a behavior of LA binding
agents. Optimization of LA-binding characteristics will be achieved by
preparing libraries of compounds made up by amino acids linked to cholic
acid scaffold. The libraries will be screened for LA binding using
affinity chromatography. The affinity chromatography stationary phase
will be made up of LA immobilized through hydrophobic interactions of
C18- silica particles or polystyrene beads. The types of amino acids
in effective LA binders will be determined via mass spectroscopy. New
LA-binding agents will be tested for the ability to sensitize Gram-
negative bacteria to hydrophobic antibiotics and/or inhibit the effects
of LA on human monocytes (specifically interleukin 1b production).
Association of PMB and the new LA-binders with LA and LA derivatives
will be compared using microtitration calorimetry.
描述:败血症影响数十万人的生活
在美国,革兰氏阴性菌引起的败血症都是由
对内毒素的脂质A(LA)部分的不利宿主免疫应答。
对LA具有高亲和力的化合物,包括多粘菌素B(PMB)和
衍生物,能够解毒LA和保护宿主免受
败血症 通过结合LA,这些化合物还使革兰氏阴性菌
细菌对疏水性抗生素的反应。 然而,PMB的治疗用途
由于其毒性而受到限制。 本研究的目的是开发
能够与LA强和选择性缔合的小分子,
用于治疗脓毒症和作为对抗细菌感染的手段。
本研究以PMB与LA的相互作用为模型,
基于胆酸的简单化合物的制备
支架,能够模拟PMB的LA结合行为,但
没有抗生素的毒性。 基于简单胆酸的LA
结合剂与报道的LA结合分子相比具有许多优点
包括:易于制备和衍生化,
生物稳定性和潜在的口服生物利用度。 胆酸
衍生物被设计为模拟PMB的构象,据信PMB是
在与LA的关系中,初步实验,
胆酸衍生物证明了它们敏化革兰氏阴性菌的能力。
阴性菌对疏水性抗生素,LA结合的行为
剂. LA结合特性的优化将通过以下方式实现:
制备由与胆酸连接的氨基酸组成的化合物文库
酸性支架 将使用以下方法筛选文库的LA结合:
亲和层析 亲和色谱固定相
将由通过疏水相互作用固定的LA组成,
C18-二氧化硅颗粒或聚苯乙烯珠粒。 氨基酸的种类
将通过质谱法测定有效LA结合剂中的含量。 新
将测试LA结合剂致敏革兰氏阴性杆菌的能力。
对疏水性抗生素呈阴性的细菌和/或抑制作用
LA对人单核细胞(特别是白细胞介素1b的生产)。
PMB和新的LA结合剂与LA和LA衍生物的缔合
将使用微量滴定量热法进行比较。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
PAUL B SAVAGE其他文献
PAUL B SAVAGE的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('PAUL B SAVAGE', 18)}}的其他基金
Carbohydrate epitope discovery via chemical synthesis
通过化学合成发现碳水化合物表位
- 批准号:
10549645 - 财政年份:2023
- 资助金额:
$ 16.45万 - 项目类别:
Development of Novel Antimicrobial Peptide Mimics
新型抗菌肽模拟物的开发
- 批准号:
7645275 - 财政年份:2009
- 资助金额:
$ 16.45万 - 项目类别:
Development of Novel Antimicrobial Peptide Mimics
新型抗菌肽模拟物的开发
- 批准号:
7928810 - 财政年份:2009
- 资助金额:
$ 16.45万 - 项目类别:
Development of Novel Antimicrobial Peptide Mimics
新型抗菌肽模拟物的开发
- 批准号:
8134342 - 财政年份:2009
- 资助金额:
$ 16.45万 - 项目类别:
相似海外基金
CAREER: Frequency Agile Real-Time Reconfigurable RF Analog Co-Processor Design Leveraging Engineered Nanoparticle and 3D Printing
职业:利用工程纳米颗粒和 3D 打印进行频率捷变实时可重构射频模拟协处理器设计
- 批准号:
2340268 - 财政年份:2024
- 资助金额:
$ 16.45万 - 项目类别:
Continuing Grant
Collaborative Research: Moire Exciton-polariton for Analog Quantum Simulation
合作研究:用于模拟量子模拟的莫尔激子极化
- 批准号:
2344658 - 财政年份:2024
- 资助金额:
$ 16.45万 - 项目类别:
Standard Grant
SBIR Phase I: Silane Recycling from Decommissioned Photovoltaics using Microgravity-analog Fluidized Bed Reactor with Sonication.
SBIR 第一阶段:使用超声处理的微重力模拟流化床反应器从退役光伏发电中回收硅烷。
- 批准号:
2323566 - 财政年份:2024
- 资助金额:
$ 16.45万 - 项目类别:
Standard Grant
Collaborative Research: Moire Exciton-polariton for Analog Quantum Simulation
合作研究:用于模拟量子模拟的莫尔激子极化
- 批准号:
2344659 - 财政年份:2024
- 资助金额:
$ 16.45万 - 项目类别:
Standard Grant
Pitch Monitor for Picosecond Electron Bunches with BPM Signal Processing with Analog RF circuits
用于皮秒电子束的节距监视器,具有 BPM 信号处理和模拟 RF 电路
- 批准号:
23H03667 - 财政年份:2023
- 资助金额:
$ 16.45万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
NSFGEO-NERC Solving the enigma of the Miocene South Asian monsoon conundrum. An analog to our future
NSFGEO-NERC 解决中新世南亚季风难题。
- 批准号:
NE/X015505/1 - 财政年份:2023
- 资助金额:
$ 16.45万 - 项目类别:
Research Grant
I-Corps: Analog Layout Design Suite
I-Corps:模拟布局设计套件
- 批准号:
2310607 - 财政年份:2023
- 资助金额:
$ 16.45万 - 项目类别:
Standard Grant
CAREER: Universal Design Automation Framework for Analog Integrated Systems
职业:模拟集成系统的通用设计自动化框架
- 批准号:
2239033 - 财政年份:2023
- 资助金额:
$ 16.45万 - 项目类别:
Continuing Grant
A Vitamin K analog countermeasure for organophosphate poisoning
维生素 K 类似物治疗有机磷中毒的对策
- 批准号:
10602913 - 财政年份:2023
- 资助金额:
$ 16.45万 - 项目类别:
Collaborative Research: Electronic Analog & Hybrid Computing for Power & Energy Systems
合作研究:电子模拟
- 批准号:
2305431 - 财政年份:2023
- 资助金额:
$ 16.45万 - 项目类别:
Standard Grant