CD4 MIMETICS AS A POTENTIAL TREATMENT FOR MS

CD4 模拟物作为多发性硬化症的潜在治疗方法

• 批准号: 6187181
• 负责人: BRADFORD A JAMESON
• 金额: $ 20.46万
• 依托单位: MCP HAHNEMANN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-15 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6187181
• 关键词: Animalia; CD4 molecule; artificial immunosuppression; drug design /synthesis /production; experimental allergic encephalomyelitis; helper T lymphocyte; immunosuppressive; mixed lymphocyte reaction test; multiple sclerosis; nuclear magnetic resonance spectroscopy; peptide analog; synthetic peptide

DESCRIPTION: The objective of this proposal is to develop a small molecule-based treatment strategy for MS. The principal investigator will employ surface mimetics of CD4 which correspond to the CDR3-like external domain of the murine CD4 molecule (the D1 domain) which contains a hydrophilic sequence (ELENRKEE) and a hydrophobic sequence that presumably partitions itself away from the hydrophilic domain. Dr. Jameson has prepared a PGP-containing analog of the CDR3 sequence with a cysteine residue at each end which form a disulfide bond, and thus provide conformational constraint. This PGP-analog has been shown to specifically inhibit CD4-dependent responses, including MLR, and EAE. An advantage over the use of anti-CD4 antibody is that this PGP-analog primarily inhibits activated TH1 cells, thus leaving naive CD4 cell function relatively intact. Drawbacks encountered to date have included low potency of the peptide mimetics and batch-to-batch inconsistencies in the biological activity of different preparations of these analogs. NMR data suggest that the disulfide-bonded PGP-analog presents a wide range of conformations but that individual molecules are effectively locked into a given conformation. This implies that there is little control over which populations dominate, and consequently, little control over which batches will be biologically active. Dr. Jameson believes he can circumvent this problem by utilizing a peptoid template. The peptoid has an N-substituted glycine backbone which may be more amenable to manipulation, thus permitting flexible structure which will maintain the same spacing of the amino acid sidechains but without the "trapped conformations" that adversely affect the biological activity of the peptide-based analogs. The principal investigator will construct a series of peptoid mimetics of the CDR3 sequence from the murine CD4 molecule and determine the structure-activity relationship (SAR) to ascertain which peptoids have biological activity in MLR and EAE models. The ultimate objective is to apply the information obtained to therapy in multiple sclerosis.

描述：该提议的目的是开发一个小的 基于分子的治疗策略。 首席调查员将 采用与CDR3样外部相对应的CD4的表面模拟物 鼠CD4分子（D1结构域）的结构域，其中包含一个 亲水性序列（Elenrkee）和疏水序列大概是 将自己脱离亲水域。 詹姆森博士有 用半胱氨酸制备了CDR3序列的含PGP的类似物 在形成二硫键的两端残留物，从而提供 构象约束。 该PGP-Analog已被证明是专门的 抑制CD4依赖性响应，包括MLR和EAE。 优势 抗CD4抗体的使用是，该PGP-Analog主要抑制 活化的Th1细胞，因此使幼稚的CD4细胞功能相对完整。 迄今为止遇到的缺点包括肽的低效力 模拟物和批处理不一致的生物学活性 这些类似物的不同准备。 NMR数据表明 二硫键键合的PGP-Analog呈现了广泛的构象，但 单个分子有效地锁定在给定的构象中。 这 意味着几乎没有控制人群占主导地位，并且 因此，几乎没有控制哪些批次将具有生物活性。 詹姆森博士认为，他可以利用肽来解决这个问题 模板。 肽具有N-取代的甘氨酸主链，可能是 更适合操纵，从而允许柔性结构 保持相同的氨基酸Sidechains间距，但没有 “被困的构象”会对人的生物活性产生不利影响 基于肽的类似物。 首席研究员将构建一个系列 来自鼠CD4分子和 确定结构性关系（SAR）以确定哪个 肽在MLR和EAE模型中具有生物学活性。 最终 目的是将获得的信息应用于多个治疗 硬化。