Characterization and Design of Histone-Derived Antimicrobial Peptides
组蛋白衍生抗菌肽的表征和设计
基本信息
- 批准号:8957693
- 负责人:
- 金额:$ 40.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-03-15 至 2020-02-01
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAmino AcidsAnti-Bacterial AgentsAntibioticsAntimicrobial Cationic PeptidesArginineBacteriaBasic Amino AcidsBiological AssayCellsCharacteristicsChargeComplementConfocal MicroscopyDNADataDevelopmentEngineeringFamilyFundingGoalsGrantHistonesHybridsIndividualKnowledgeLearningLengthLysineMeasurementMembraneMolecularNuclear StructureOrganismPeptide SynthesisPeptidesPropertyProteinsPublic HealthResearchResearch PersonnelResistance developmentRoleSeriesSourceStructureStructure-Activity RelationshipSystemTestingTherapeutic AgentsTrainingWomanWorkantimicrobial peptidebacterial resistancebasecollegecombatcostdesignguanidiniuminsightkillingsmembrane activitymolecular dynamicsnovelpeptide structurepublic health relevancetrend
项目摘要
DESCRIPTION (provided by applicant): Bacteria that have developed resistance to conventional antibiotics are an increasing public health concern, and antimicrobial peptides (AMPs) represent a potential alternative to combat these bacteria. One intriguing family of AMPs is the histone-derived antimicrobial peptides (HDAPs). HDAPs have been isolated from natural sources, and the mechanisms for many of these peptides have been determined experimentally, such as in work performed during our previously funded AREA grant. Other work in our lab has designed a series of novel HDAPs based on histone crystal structures. However, relatively little effort has focused on the rational optimization of HDAPs to engineer more active peptides. The research in this proposal aims to address this gap by considering a systematic approach for the rational design of HDAPs. In this proposed design, we will focus on the role of three factors: the Arg composition of basic amino acids, the minimal length of active peptides and the creation of hybrid peptides. We will use a combination of bacterial assays, confocal microscopy, spectroscopic measurements, and molecular dynamics simulations to probe how each of these factors influences peptide activity on a molecular level. Although these factors are known to influence the activity of other AMPs, the structure-function relationships leading to these effects are not well understood. Thus, we expect that results from this proposed work can be generalized to give insight into the how these factors influence the activity of other AMPs. HDAPs are an ideal family of peptides to use for this purpose since they operate through different mechanisms, with some permeabilizing membranes and others translocating into cells and interacting with intracellular components. After elucidating trends for these three characteristics in HDAPs, we will combine this information to create a novel series of HDAPs that optimize the individual factors for peptide activity. We can thus validate whether this is a useful approach to peptide design in HDAPs that could be applied to other peptide systems. Together, the insight from these studies will both promote the development of HDAPs as potential therapeutic agents and provide insights into HDAP structure-function relationships that potentially can be generalized to other families of cationic AMPs. In addition to these scientific goals, this proposed research also has a strong emphasis on training as the work will be carried out by several undergraduate researchers and a few recent graduates at Wellesley College, an undergraduate women's college.
描述(由申请人提供):对常规抗生素产生耐药性的细菌是一个日益严重的公共卫生问题,抗菌肽(AMP)是对抗这些细菌的潜在替代品。一个有趣的AMP家族是组蛋白衍生的抗菌肽(HDAP)。HDAP已经从天然来源中分离出来,并且许多这些肽的机制已经通过实验确定,例如在我们先前资助的AREA资助期间进行的工作。我们实验室的其他工作是设计了一系列基于组蛋白晶体结构的新型HDAP。然而,相对较少的努力集中在HDAP的合理优化,以工程化更有活性的肽。本提案中的研究旨在通过考虑合理设计HDAP的系统方法来解决这一差距。在这个设计中,我们将重点关注三个因素的作用:碱性氨基酸的精氨酸组成,活性肽的最小长度和杂交肽的创建。我们将使用细菌检测,共聚焦显微镜,光谱测量和分子动力学模拟的组合来探测这些因素中的每一个如何在分子水平上影响肽的活性。虽然已知这些因素影响其他AMP的活性,但导致这些效应的结构-功能关系尚未得到很好的理解。因此,我们期望这项工作的结果可以推广到深入了解这些因素如何影响其他AMP的活性。HDAP是用于此目的的理想肽家族,因为它们通过不同的机制起作用,其中一些透化膜和其他转运到细胞中并与细胞内组分相互作用。在阐明HDAP中这三个特征的趋势后,我们将联合收割机结合这些信息来创建一个新的HDAP系列,优化肽活性的各个因素。因此,我们可以验证这是否是一个有用的方法,可以应用于其他肽系统的肽设计在HDAP。总之,这些研究的见解将促进HDAP作为潜在治疗剂的发展,并提供对HDAP结构-功能关系的见解,这些关系可能推广到其他阳离子AMP家族。除了这些科学目标之外,这项拟议的研究还非常强调培训,因为这项工作将由几名本科生研究人员和韦尔斯利学院(一所本科生女子学院)的几名应届毕业生进行。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Effect of proline position on the antimicrobial mechanism of buforin II.
- DOI:10.1016/j.peptides.2011.01.010
- 发表时间:2011-04
- 期刊:
- 影响因子:3
- 作者:Xie Y;Fleming E;Chen JL;Elmore DE
- 通讯作者:Elmore DE
Modular analysis of hipposin, a histone-derived antimicrobial peptide consisting of membrane translocating and membrane permeabilizing fragments.
- DOI:10.1016/j.bbamem.2014.04.010
- 发表时间:2014-09
- 期刊:
- 影响因子:0
- 作者:Bustillo ME;Fischer AL;LaBouyer MA;Klaips JA;Webb AC;Elmore DE
- 通讯作者:Elmore DE
Role of arginine and lysine in the antimicrobial mechanism of histone-derived antimicrobial peptides.
- DOI:10.1016/j.febslet.2015.11.002
- 发表时间:2015-12-21
- 期刊:
- 影响因子:3.5
- 作者:Cutrona KJ;Kaufman BA;Figueroa DM;Elmore DE
- 通讯作者:Elmore DE
Insights into buforin II membrane translocation from molecular dynamics simulations.
- DOI:10.1016/j.peptides.2012.09.022
- 发表时间:2012-12
- 期刊:
- 影响因子:3
- 作者:Elmore DE
- 通讯作者:Elmore DE
Measuring peptide translocation into large unilamellar vesicles.
测量肽转位到大单层囊泡中。
- DOI:10.3791/3571
- 发表时间:2012
- 期刊:
- 影响因子:0
- 作者:Spinella,SaraA;Nelson,RachelB;Elmore,DonaldE
- 通讯作者:Elmore,DonaldE
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Donald E. Elmore其他文献
Computational Modeling: Exploring How Mini Reserach Projects and Classroom Activities Impact Student Learning
- DOI:
10.1016/j.bpj.2018.11.2427 - 发表时间:
2019-02-15 - 期刊:
- 影响因子:
- 作者:
Shelby N. Kranc;Donald E. Elmore;Martin Berryman;Mala L. Radhakrishnan - 通讯作者:
Mala L. Radhakrishnan
Exploring the Co-Mutlimerization of bCNG Channels
- DOI:
10.1016/j.bpj.2011.11.677 - 发表时间:
2012-01-31 - 期刊:
- 影响因子:
- 作者:
Hannah R. Malcolm;Donald E. Elmore;Joshua A. Maurer - 通讯作者:
Joshua A. Maurer
Synergy between Histone-Derived Antimicrobial Peptides and Conventional Antibiotics
- DOI:
10.1016/j.bpj.2020.11.1061 - 发表时间:
2021-02-12 - 期刊:
- 影响因子:
- 作者:
Jane Zen;Louise E. Darling;Donald E. Elmore - 通讯作者:
Donald E. Elmore
Macromolecular Crowding Effects on Energetic Residue Contributions to Peptide-Nucleic Acid Interactions
- DOI:
10.1016/j.bpj.2017.11.2520 - 发表时间:
2018-02-02 - 期刊:
- 影响因子:
- 作者:
Carla P. Perez;Donald E. Elmore;Mala L. Radhakrishnan - 通讯作者:
Mala L. Radhakrishnan
Characterization of Hybrids Made from Two Membrane Translocating Antimicrobial Peptides
- DOI:
10.1016/j.bpj.2018.11.489 - 发表时间:
2019-02-15 - 期刊:
- 影响因子:
- 作者:
Ju Young Kwag;Hannah Klim;Donald E. Elmore - 通讯作者:
Donald E. Elmore
Donald E. Elmore的其他文献
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{{ truncateString('Donald E. Elmore', 18)}}的其他基金
Systematic Design of Histone-Derived Antimicrobial Peptides
组蛋白衍生抗菌肽的系统设计
- 批准号:
10438240 - 财政年份:2022
- 资助金额:
$ 40.93万 - 项目类别:
Characterization and Design of Histone-Derived Antimicrobial Peptides
组蛋白衍生抗菌肽的表征和设计
- 批准号:
7881187 - 财政年份:2010
- 资助金额:
$ 40.93万 - 项目类别:
MOLECULAR DYNAMICS SIMULATIONS OF BUFORIN II TRANSLOCATION
蟾蜍素 II 易位的分子动力学模拟
- 批准号:
8171887 - 财政年份:2010
- 资助金额:
$ 40.93万 - 项目类别:
MOLECULAR DYNAMICS SIMULATIONS OF BUFORIN II TRANSLOCATION
蟾蜍素 II 易位的分子动力学模拟
- 批准号:
7956348 - 财政年份:2009
- 资助金额:
$ 40.93万 - 项目类别:
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