Targeted Modification of Membrane Lipids
Targeted Modification of Membrane Lipids
批准号:
10176514
负责人:
Jianmin Gao
金额:
$31.3万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-09-01 至 2023-05-31
关键词:
AdoptedAnimal ModelAntibiotic ResistanceBacteriaBacterial Antibiotic ResistanceBacterial InfectionsBicyclingBindingBiologicalBiologyCationsCell membraneCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeChargeChemistryComputer ModelsCyclic PeptidesDefensinsDrug resistanceEligibility DeterminationEntropyEvolutionHost DefenseHost Defense MechanismHumanImmune systemImmunityIn VitroInfectionInvadedLibrariesLipidsLysineMammalian CellMasksMediatingMembraneMembrane LipidsMethodologyModelingModificationMusMutationNatural ImmunityNatural ProductsOrganismPeptide LibraryPeptidesPeriodicityPhosphatidylglycerolsPotassiumReportingResearchResistanceSideSite-Directed MutagenesisSocietiesStaphylococcus aureusStructureTestingWorkaqueousbactericidebasebiomaterial compatibilitycell killingdesignefficacy testingemerging antibiotic resistancefight againstgenome sequencingin vivoinnovationmouse modelneutrophilnovelnovel strategiespathogenpathogenic bacteriaresistance mechanismresistant strainscaffoldscreeningsmall moleculesuccesswhole genome
中文摘要
膜脂的靶向修饰
英文摘要
Targeted Modification of Membrane Lipids
Project Summary
The lipid composition of membranes has critical ramifications in biology. It has been long known that
bacterial and mammalian cells harbor a different set of lipids in their membranes. While a mammalian cell
membrane is largely composed of zwitterionic lipids, bacterial cells typically display anionic lipids in large
quantities. Taking advantage of this difference, many organisms have evolved cationic host defense peptides
(HDPs), which serve as the frontline of the innate immunity to fend off invading bacterial pathogens. For
example, human neutrophils rely on cationic defensins for bacterial cell killing and clearance. To acquire
resistance against cationic HDPs, selected bacterial species synthesize the lipid Lys-PG, which carries a net
positive charge. We hypothesize that synthetic molecules that bind Lys-PG and consequently mask its net
charge will re-sensitize the bacterial cells to killing by HDPs. To test the hypothesis, we will develop synthetic
modifiers of Lys-PG by introducing reversible covalent warheads into well-structured scaffolds. Further we will
test the efficacy of Lys-PG modification in vitro and in mouse infection models. The specific aims are: 1) we will
use a known, foldable cyclic peptide scaffold to assemble multiple side chains for Lys-PG modification.
Computational modeling will be integrated with experimental characterization to optimize for Lys-PG binding; 2)
we will develop potent and specific modifiers of Lys-PG by screening novel bicyclic peptide libraries. This part
of the proposal will be based on a powerful peptide bicyclization strategy recently developed by our group; 3)
the Lys-PG modifiers developed in 1) and 2) will be tested for their capability to potentiate the bactericidal
activity of several HDPs and neutrophils. Their efficacy to facilitate bacterial clearance will be further examined
in mouse models of infection. With success, the proposed work will yield a novel strategy to fight against the
drug-resistance strains of bacterial pathogens. Although the proposed work focuses on Lys-PG, the
methodology developed here should be extendable to other lipid modifications of biological significance.
期刊论文(21)
专著(0)
科研奖励(0)
会议论文
登录
查看更多内容
DOI:
10.1002/chem.201502077
发表时间:
2015-10-12
期刊:
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子:
--
作者:
[Bandyopadhyay A, Gao J]
通讯作者:
Gao J
DOI:
10.1021/acs.biochem.7b00702
发表时间:
2017-10-10
期刊:
Biochemistry
影响因子:
2.9
作者:
[Gao J]
通讯作者:
Gao J
DOI:
10.1021/jacs.6b11115
发表时间:
2017-01-18
期刊:
Journal of the American Chemical Society
影响因子:
15
作者:
[Bandyopadhyay A, Cambray S, Gao J]
通讯作者:
Gao J
DOI:
10.1002/cbic.201600667
发表时间:
2017-03-02
期刊:
Chembiochem : a European journal of chemical biology
影响因子:
--
作者:
[Hosseini AS, Wang W, Haeffner F, Gao J]
通讯作者:
Gao J
Targeting biomolecules with reversible covalent chemistry.
用可逆的共价化学靶向生物分子。
DOI:
10.1016/j.cbpa.2016.08.011
发表时间:
2016-10
期刊:
CURRENT OPINION IN CHEMICAL BIOLOGY
影响因子:
7.8
作者:
[Bandyopadhyay, Anupam, Gao, Jianmin]
通讯作者:
Gao, Jianmin
共 15 条
Novel Phage Display Platforms to Overcome Colistin Resistance
-
批准号:10405089
-
项目类别:
-
资助金额:$29.74万
-
财政年份:2019
-
负责人:Jianmin Gao
-
依托单位:
Novel Phage Display Platforms to Overcome Colistin Resistance
-
批准号:10165742
-
项目类别:
-
资助金额:$29.74万
-
财政年份:2019
-
负责人:Jianmin Gao
-
依托单位:
Small Molecule Receptors for Membrane Lipids
-
批准号:8668104
-
项目类别:
-
资助金额:$25.67万
-
财政年份:2012
-
负责人:Jianmin Gao
-
依托单位:
Small Molecule Receptors for Membrane Lipids
-
批准号:8345247
-
项目类别:
-
资助金额:$25.67万
-
财政年份:2012
-
负责人:Jianmin Gao
-
依托单位:
Small Molecule Receptors for Membrane Lipids
-
批准号:8530255
-
项目类别:
-
资助金额:$24.77万
-
财政年份:2012
-
负责人:Jianmin Gao
-
依托单位:
海外基金