CARBOHYDRATE-BASED PEPTIDOMIMETICS TO PREVENT CANDIDIAS

基于碳水化合物的拟肽预防念珠菌

• 批准号: 6362941
• 负责人: GURRINDER S BEDI
• 金额: $ 13.44万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6362941
• 关键词: Candida albicans; antigen antibody reaction; antiidiotype antibody; biomimetics; biotechnology; calorimetry; candidiasis; cell adhesion; chemoprevention; circular dichroism; disease /disorder prevention /control; drug design /synthesis /production; host organism interaction; laboratory mouse; laboratory rat; ligands; oligosaccharides; oral pharyngeal disorder; peptide chemical synthesis; peptide library; protein sequence; protein structure function; virulence

Cell surface carbohydrates (oligosaccharides) play significant roles in a wide range of cellular recognition events. The exquisite specificity of such interactions has led to development of several promising carbohydrate-based therapeutics. However, the high cost of synthesizing oligosaccharides has proven to be significant barrier to more wide-spread use of this approach. Moreover, In instances where a therapeutic is optimally delivered via a "gene therapy" approach, there is no direct way of delivering a carbohydrate based agent. There are several examples of molecular mimicry in which unrelated molecules share sufficient surface topology to be considered functional equivalents. Peptide mimetics of a carbohydrate structure have been identified, and these would be relatively inexpensive to produce and could be delivered in vivo by standard gene therapy approaches. Candida albicans Is an opportunistic fungus which can cause life-threatening infection, particularly among immunocompromised individuals. The virulence of this organism is related, in part, to Its ability to adhere to host tissue surfaces via the recognition carbohydrate structures which decorate the cell-surfaces of both fungus and host. The goal of this exploratory research grant proposal is to test the hypothesis that peptidomimetics of specific cell-surface carbohydrate structures can be used to reduce the level of the in vivo oral candidiasis which accompanies (experimental) salivary gland hypofunction. We will use two complementary approaches to generate the peptidomimetics; (1) combinatorial libraries will be screened for peptides which bind to either lectins or antibodies which recognize the oligosaccharide of interest; and (2) peptide sequence will be derived from antibody hypervariable region sequences of anti-ldiotypic antibodies prepared against appropriate anti-oligosaccharide antibodies. The secondary structure of each peptide will be experimentally determined and kinetic parameters which quantitatively describe the interaction of each peptide with its cognate lectin or antibody will be obtained. Mimetics which cause significant reduction of Candida adhesion to buccal epithelial cells in vitro will then be tested in a surgically desalivated rat model system used previously in our laboratories.

细胞表面碳水化合物（低聚糖）在多种细胞识别事件中发挥着重要作用。 这种相互作用的精确特异性导致了几种有前途的基于碳水化合物的疗法的开发。 然而，合成寡糖的高成本已被证明是更广泛使用这种方法的重大障碍。 此外，在通过“基因疗法”方法最佳地递送治疗剂的情况下，不存在递送基于碳水化合物的药剂的直接方法。 有几个分子拟态的例子，其中不相关的分子共享足够的表面拓扑结构以被视为功能等价物。 碳水化合物结构的肽模拟物已经被鉴定出来，这些模拟物的生产成本相对较低，并且可以通过标准基因治疗方法在体内递送。白色念珠菌是一种机会性真菌，可引起危及生命的感染，特别是在免疫功能低下的个体中。 该生物体的毒力部分与其通过识别装饰真菌和宿主细胞表面的碳水化合物结构粘附到宿主组织表面的能力有关。 这项探索性研究资助提案的目的是检验以下假设：特定细胞表面碳水化合物结构的肽模拟物可用于降低伴随（实验性）唾液腺功能减退的体内口腔念珠菌病的水平。 我们将使用两种互补的方法来生成肽模拟物； (1) 组合文库将筛选与凝集素或识别目标寡糖的抗体结合的肽； (2)肽序列源自针对适当的抗寡糖抗体制备的抗独特型抗体的抗体高变区序列。 将通过实验确定每种肽的二级结构，并获得定量描述每种肽与其同源凝集素或抗体相互作用的动力学参数。 然后，将在我们实验室先前使用的手术脱唾液大鼠模型系统中测试在体外引起念珠菌对颊上皮细胞粘附显着减少的模拟物。