New Peptides for the Treatment of Multiple Sclerosis

治疗多发性硬化症的新肽

• 批准号: 8236305
• 负责人: Christine Beeton
• 金额: $ 39.67万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236305
• 关键词: Acute; Adverse effects; Affect; Animal Model; Arrhythmia; Arthritis; Binding Sites; Biological; Carbon; Cardiotoxicity; Cell Enlargement; Cells; Central Nervous System Diseases; Cessation of life; Charge; Chlamydia; Chlamydia trachomatis; Chronic; Coupled; Data; Delayed Hypersensitivity; Development; Disease; Docking; Drug Formulations; Drug Kinetics; Experimental Autoimmune Encephalomyelitis; FDA approved; Generations; Goals; Half-Life; Human; Hydrolysis; Immune response; Immunomodulators; Immunosuppression; Immunotherapy; In Vitro; Infection; Inflammatory; Influenza; Injection of therapeutic agent; Intervention; Ion Channel; Kv1.2' channel; Lymphocyte Activation; Malignant Neoplasms; Modeling; Modification; Molecular Models; Multiple Sclerosis; Mus; Pathogenesis; Peptides; Pharmaceutical Preparations; Play; Polyethylene Glycols; Potassium Channel; Pristane; Production; Proteins; Public Health; Rattus; Relapse; Relapsing-Remitting Multiple Sclerosis; Resolution; Role; Safety; Sea Anemones; Seizures; Site; Specificity; Structure; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Temperature; Testing; Therapeutic Intervention; Tissues; Toxic effect; United States; Viral; Voltage-Gated Potassium Channel; adduct; analog; base; cell motility; channel blockers; compliance behavior; cost; cytokine; design; disability; high risk; immunogenic; immunogenicity; improved; in vitro testing; in vivo; meetings; molecular dynamics; molecular modeling; nonhuman primate; novel; novel therapeutics; oxidation; patch clamp; pathogen; polypeptide; safety study; terminally differentiated effector memory (TEM) T cells; tool

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that leads to severe disability and death. Of the current FDA-approved medications for relapsing forms of MS, all have significant side effects. We propose to use a multi-disciplinary, structure-based approach to developing novel polypeptide blockers of the voltage-gated potassium channel Kv1.3 as new interventions for MS. This channel is highly expressed by terminally-differentiated effector memory T (TEM) lymphocytes that play a major role in MS pathogenesis. Extensive in vitro and in vivo efficacy and safety studies have validated Kv1.3 as a target for immunotherapy and shown that the peptide ShK, originally isolated from a sea anemone, is not only a potent blocker of this channel but also an effective immunomodulator. However, its lack of selectivity for Kv1.3 channels creates a high risk of toxicity through interactions with other potassium channels. We have developed a first generation of synthetic analogs of ShK by modifying its N-terminus with non-protein adducts. These analogs show enhanced specificity for Kv1.3 over other ion channels while retaining picomolar potency, and they selectively suppress cytokine production and proliferation of human TEM cells without affecting other T cell subsets. In rat studies, one of these analogs (ShK-186) suppresses TEM cell enlargement and motility in inflamed tissues, inhibits delayed-type hypersensitivity, and effectively treats chronic-relapsing experimental autoimmune encephalomyelitis (CR-EAE; a model of MS) and pristane-induced arthritis. While ShK-186 and related analogs have an excellent safety profile in rats and do not compromise the protective immune response to acute infection with viral (influenza) or bacterial (chlamydia) pathogens, they suffer from several limitations: (i) they are sensitive to changes in pH and temperature; (ii) they have very short in vivo half-lives; (iii) a phosphorylated residue on ShK-186 can be dephosphorylated; (iv) they contain a Met residue that is susceptible to oxidation; and (v) their non-protein adducts are immunogenic. We now propose to design, generate, and evaluate novel analogs of ShK. Under Specific Aim 1 we will use molecular modeling and high-resolution NMR to determine the docking configuration of ShK analogs on Kv1.3 and thereby to design and synthesize more potent and selective N- and C-terminally extended ShK analogs. Under Specific Aim 2 we will assess ShK analogs for their in vitro potency, selectivity, stability, and effects on T lymphocyte activation, and PEGylate them to increase their circulating half-life. Under Specific Aim 3 we will evaluate the most potent and selective ShK analogs in vivo for pharmacokinetics, immunogenicity, safety, and efficacy. This project will generate novel peptide blockers of Kv1.3, which we believe will be valuable leads in the development of new treatments for MS and other chronic inflammatory diseases. PUBLIC HEALTH RELEVANCE: Multiple sclerosis is a chronic inflammatory disease of the central nervous system that affects approximately 400,000 people in the United States alone and more than 2.1 million people worldwide. Our goal is to design new peptides that target inflammatory cells for the treatment of multiple sclerosis, and possibly other chronic inflammatory diseases. Such new therapeutic tools would have tremendous benefits for public health.

描述(申请人提供)：多发性硬化症(MS)是一种慢性炎症性中枢神经系统疾病，导致严重残疾和死亡。在目前FDA批准的治疗复发性多发性硬化症的药物中，都有显著的副作用。我们建议使用多学科、基于结构的方法来开发电压门控钾通道Kv1.3的新型多肽阻滞剂，作为治疗MS的新干预措施。该通道由在MS发病机制中发挥主要作用的终末分化的效应记忆T(TEM)淋巴细胞高度表达。广泛的体外和体内有效性和安全性研究证实Kv1.3是免疫治疗的靶点，并表明最初从海葵中分离出来的多肽ShK不仅是这一通道的有效阻滞剂，而且是有效的免疫调节剂。然而，它缺乏对Kv1.3通道的选择性，通过与其他钾通道的相互作用产生了高毒性风险。我们开发了第一代ShK的合成类似物，通过用非蛋白质加合物修饰其N-末端。这些类似物在保持皮摩尔效力的同时，显示出比其他离子通道更强的Kv1.3的特异性，它们选择性地抑制细胞因子的产生和人横纹夜蛾细胞的增殖，而不影响其他T细胞亚群。在大鼠研究中，其中一种类似物(ShK-186)抑制炎症组织中透射电子显微镜细胞的扩大和运动，抑制迟发型超敏反应，并有效治疗慢性复发性实验性自身免疫性脑脊髓炎(CR-EAE；多发性硬化症的模型)和Pristane诱导的关节炎。虽然ShK-186和相关类似物在大鼠身上具有良好的安全性，并且不影响对病毒(流感)或细菌(衣原体)病原体的急性感染的保护性免疫反应，但它们受到几个限制：(I)它们对pH和温度的变化很敏感；(Ii)它们在体内的半衰期非常短；(Iii)ShK-186上的磷酸化残基可以被去磷酸化；(Iv)它们含有易于氧化的Met残基；以及(V)它们的非蛋白加合物具有免疫原性。我们现在建议设计、生成和评估ShK的新类似物。在特定目标1下，我们将使用分子模拟和高分辨率核磁共振来确定ShK类似物在Kv1.3上的对接构型，从而设计和合成更有效和更具选择性的N-末端和C-末端延伸的ShK类似物。在特定目标2下，我们将评估ShK类似物的体外效力、选择性、稳定性和对T淋巴细胞激活的影响，并对它们进行聚乙二醇化以延长其循环半衰期。在特定目标3下，我们将评估体内最有效和最有选择性的ShK类似物的药代动力学、免疫原性、安全性和有效性。该项目将产生Kv1.3的新型多肽阻滞剂，我们相信这将是开发多发性硬化症和其他慢性炎症性疾病新疗法的宝贵线索。 公共卫生相关性：多发性硬化症是一种慢性中枢神经系统炎症性疾病，仅在美国就有大约40万人受到影响，全世界有超过210万人受到影响。我们的目标是设计以炎性细胞为靶点的新多肽，用于治疗多发性硬化症，可能还有其他慢性炎症性疾病。这种新的治疗工具将对公共健康产生巨大的好处。