Solid-state NMR studies of antimicrobial peptides
抗菌肽的固态核磁共振研究
基本信息
- 批准号:7175329
- 负责人:
- 金额:$ 21.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-02-01 至 2008-06-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAffectAlamethicinAmino Acid SequenceAmino AcidsAmphibiaAnimalsAnti-Bacterial AgentsAnti-Retroviral AgentsAntibiotic ResistanceAntibioticsAntifungal AgentsAntiviral AgentsBackBacteriaBindingBiologicalBiological AssayC14 isotopeCaliberCarbonCarpetCell membraneCellsCharacteristicsChargeChemicalsCholesterolClinical TrialsColony-forming unitsComplexCyclic PeptidesDataDecompression SicknessDefensinsDependenceDepthDiffusionDimyristoylphosphatidylcholineDisruptionElectrostaticsElementsErythrocyte MembraneErythrocytesFaceFamilyFamily suidaeFluorescenceFree EnergyGram-Negative BacteriaGram-Positive BacteriaGramicidinHIV-1Helix (Snails)HumanImmune systemIn VitroInfectionInsectaJ-Chain ImmunoglobulinsKnowledgeLabelLengthLeukocytesLipid BilayersLipidsLiquid substanceMacaca mulattaMammalian CellMammalsMeasurementMeasuresMembraneMembrane LipidsMembrane PotentialsMethicillin ResistanceMicrobeMinimum Inhibitory Concentration measurementModelingMolecularMolecular ConformationMotionNMR SpectroscopyNeutronsNisinNuclear Magnetic ResonanceNumbersOrganismParentsPeptide AntibioticsPeptide ConformationPeptidesPhasePlayPrincipal InvestigatorPropertyProteinsRangeRateResearchResistanceResistance developmentRoleRotationSamplingShapesSideSiteSodium ChlorideSolutionsSpeedStaphylococcus aureusStructureStructure-Activity RelationshipSurfaceSurveysSystemTestingThinkingTimeTopical AntibioticToxic effectViralVirusWateranalogantimicrobialantimicrobial peptideaqueousarctic environmentargininamidearginyllysinebactericidebasebeta pleated sheetcecropincostcytotoxicitydensitydermaseptindermaseptin sdesigndimerdimyristoylphosphatidylglyceroldisulfide bondear helixenantiomerfungushuman neutrophil peptide 3improvedinsightinterestkillingsmagaininmicrobialmicrobicidemicroorganismneglectovispirinpathogenpeptide analogpeptide structurephysical propertypreventprogesterone 11-hemisuccinate-(2-iodohistamine)protegrin PG-1protegrinsquantumradius bone structurereceptorresearch studysizesmall moleculesolid statetachyplesintheta-defensintooltritrpticin
项目摘要
DESCRIPTION (provided by applicant): Antimicrobial peptides are evolutionarily highly preserved elements of the innate immune system in animals. They kill a wide range of microbial organisms such as bacteria, viruses, and fungi with high potency and speed. Their remarkable ability to prevent pathogenic resistance makes these peptides a viable alternative to conventional antibiotics. The broad objective of this research is to elucidate the structural basis for antimicrobial action, so that new and improved antibiotics with strong microbiocidal activity but low cytotoxicity to mammalian cells may be designed.
The central hypothesis of this project is that antimicrobial peptides share common mechanisms of action that derive from the special characteristics of microbial membranes such as radius of curvature, surface charge, and lack of cholesterol, characteristics that are distinct from mammalian membranes. To test this hypothesis, we will specifically determine the interactions of two representative peptides with lipid bilayers that mimic bacterial, retroviral, and human erythrocyte membranes; determine the orientation topology of these peptides in these various lipid membranes; and measure the secondary structure and aggregation state of these peptides. The peptides of choice are protegrin-1 (PG-1) and rhesus theta-defensin 1 (RTD-1), which both possess a disulfide-bond stabilized beta-sheet conformation that is common to a large number of antimicrobial peptides, including the defensins found in humans.
We will use an integrated solid-state nuclear magnetic resonance (NMR) approach to study the mechanism of action of these two beta-sheet peptides. The important lipid factors in antimicrobial selectivity will be identified by studying the lipid-peptide interactions in lipids with defined membrane curvature, cholesterol content, and anionic surface charges. 31P and 2H NMR will be used as the main probes for the lipid-peptide interaction. Information on the peptide orientation in the lipid bilayer is important for understanding whether the peptides disrupt the cell membrane by pore formation or by micellization. This information will be obtained by 13C and 15N NMR experiments using both oriented and unoriented static samples. The ability to extract molecular orientation using unoriented samples will allow us to measure the concentration-dependence and membrane-curvature-dependence of the peptide orientation. The secondary structure and aggregation of PG-1 and RTD-1 in lipid bilayers will be determined from NMR isotropic chemical shifts and multiple-quantum experiments, respectively. Together, the new structural information, correlated with the characteristics of lipid membranes, will significantly advance our understanding of the mechanism of action of beta-sheet antimicrobial peptides. Moreover, the proposed research will fill our knowledge gap of how beta-sheet peptides interact with lipid bilayers in general.
描述(由申请人提供):抗菌肽是动物先天免疫系统中进化高度保存的元素。它们能高效、快速地杀死多种微生物,如细菌、病毒和真菌。这些肽具有显著的预防致病性耐药性的能力,这使它们成为传统抗生素的可行替代品。本研究的主要目的是阐明抗菌作用的结构基础,从而设计出具有强杀微生物活性但对哺乳动物细胞毒性低的新型和改良抗生素。
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)
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Mei Hong其他文献
Mei Hong的其他文献
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