DEFENSINS, BACTENECINS AND PERIODONTAL DISEASES
防御素、杆菌肽和牙周疾病
基本信息
- 批准号:6296240
- 负责人:
- 金额:$ 16.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1997
- 资助国家:美国
- 起止时间:1997-08-01 至 2000-04-30
- 项目状态:已结题
- 来源:
- 关键词:Actinobacillus actinomycetemcomitans Bacteroides gingivalis Candida albicans X ray crystallography antibiotics bactericidal immunity chemical stability chemical substitution chemoattractants circular dichroism conformation drug design /synthesis /production human tissue infrared spectrometry neutrophil nuclear magnetic resonance spectroscopy peptide analog peptide chemical synthesis periodontitis polymerase chain reaction protein sequence protein structure function recombinant DNA site directed mutagenesis synthetic peptide
项目摘要
The long range goal of this project is to systematically study the
structural and molecular biology of "defensins and bactenecins", the
antimicrobial cationic polypeptides present in the granules of
neutrophils. These studies will help identify, design, develop and
evaluate a new class of nontoxic antibiotics to be used to defend against
periodontal pathogens including Actinobacillus actinomycetemcomitans and
Porphyromonas gingivalis as well as opportunistic pathogens such as
Candida albicans.
Defensins and bactenecins are delivered to vacuoles containing the
ingested microorganisms during phagocytosis and are released into the
extracellular fluids when neutrophils are stimulated by secretagogues.
They interact with the membranes of microbes, alter membrane permeability
and ionic gradient, and further cause impairment of the function of the
respiratory chain and other energy dependent activities in the inner
membranes. They play a major role in host defense, inflammation and
restoration of the altered homeostatic condition by their ability to kill
invading microbes. This suggests a rationale for selection of these
molecules for our present studies and the importance of these molecules
in controlling oral infections by these organisms including periodontal
disease.
The highly conserved disulfides, glycines and the charged residues in
defensins, and the repeating Pro-Arg-Pro triplets spaced by a single
hydrophobic residue in bactenecins, provide rigid structures for these
molecules to overcome the adaptive microbial resistance to organic
antibiotics. These unique conserved structural elements also suggest
that their microbicidal functions are indeed dependent on a specific
structural feature and a particular charge distribution. The structural
diversity observed in the primary sequence of these polypeptides is
reflected in wide variations in their biological activity. This
functional diversity is clearly a consequence of subtle variations in the
size, sequence, fine structural motifs and side-chain topography of these
molecules. This project involves synthesis of defensins, bactenecins and
peptide analogs by both chemical and genetic engineering techniques,
structure determination by spectroscopic methods (NMR, FTIR, CD),
computer modeling and crystal structure analysis, and assessment of in
vitro cidal activity of these molecules.
The information to be obtained from structure-function analyses will
permit the design and synthesis of stereochemically constrained peptide
analogs of defensins and bactenecins which could elicit enhanced and
prolonged activity. These new oral antibiotics may be useful for the
control and treatment of periodontal disease and other oral infections.
In addition, the molecular biology studies would delineate the cDNA and
the recombinant DNA encoding the sequences of the active analogs and lead
to gene therapy approaches for similar clinical applications.
该项目的长期目标是系统地研究
防御素和杆菌素的结构和分子生物学,
存在于颗粒中的抗微生物阳离子多肽
中性粒细胞 这些研究将有助于确定、设计、开发和
评估一种新的无毒抗生素,用于预防
牙周病原体,包括伴放线放线杆菌,
牙龈卟啉单胞菌以及机会致病菌,
白念珠菌
防御素和杆菌素被递送到含有
在吞噬过程中摄入的微生物,并被释放到
当中性粒细胞被促分泌素刺激时,细胞外液。
它们与微生物的细胞膜相互作用,改变细胞膜的渗透性
和离子梯度,并进一步导致功能的损害,
呼吸链和其他依赖能量的活动
膜。 它们在宿主防御、炎症和免疫反应中发挥重要作用。
通过它们的杀伤能力恢复改变的体内平衡状态
入侵的微生物 这表明了选择这些
分子为我们目前的研究和这些分子的重要性
在控制口腔感染的这些生物体,包括牙周
疾病
高度保守的二硫键,甘氨酸和带电残基,
防御素,以及重复的Pro-Arg-Pro三联体,
杆菌素中疏水残基为这些提供了刚性结构
分子,以克服适应性微生物对有机
抗生素 这些独特的保守结构元件也表明
它们的杀微生物功能确实依赖于一种特定的
结构特征和特定电荷分布。 结构性
在这些多肽的一级序列中观察到的多样性
反映在其生物活性的广泛变化中。 这
功能多样性显然是一个微妙的变化的结果,
它们的大小、序列、精细结构基序和侧链形貌
分子。 该项目涉及合成防御素,bactenecins和
通过化学和基因工程技术,
通过光谱方法(NMR、FTIR、CD)进行结构测定,
计算机建模和晶体结构分析,并评估
这些分子的体外杀灭活性。
从结构-功能分析中获得的信息将
允许设计和合成立体化学限制的肽
防御素和杆菌素的类似物,
长期活动。 这些新的口服抗生素可能对
控制和治疗牙周病和其他口腔感染。
此外,分子生物学研究将描绘cDNA,
编码活性类似物和前导序列的重组DNA
用于类似临床应用的基因治疗方法。
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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{{ truncateString('ANTONY R PERIATHAMBY', 18)}}的其他基金
Novel Bifunctional Molecules for Intraoral Drug Delivery
用于口腔内药物输送的新型双功能分子
- 批准号:
6459475 - 财政年份:2002
- 资助金额:
$ 16.97万 - 项目类别:
Novel Bifunctional Molecules for Intraoral Drug Delivery
用于口腔内药物输送的新型双功能分子
- 批准号:
6622956 - 财政年份:2002
- 资助金额:
$ 16.97万 - 项目类别:
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