New Peptides for the Treatment of Multiple Sclerosis

治疗多发性硬化症的新肽

• 批准号: 8473290
• 负责人: Christine Beeton
• 金额: $ 35.12万
• 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/8473290
• 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.

描述（由申请人提供）：多发性硬化症（MS）是中枢神经系统的慢性炎症性疾病，导致严重的残疾和死亡。在当前FDA批准的用于复发形式的MS的药物中，都具有显着的副作用。我们建议使用基于结构的多学科，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MS的新干预措施。该通道由末端分化的效应子记忆T（TEM）淋巴细胞高度表达，该淋巴细胞在MS发病机理中起主要作用。广泛的体外和体内功效和安全性研究已验证KV1.3作为免疫疗法的靶标，并表明最初从海葵中分离出来的肽SHK不仅是该通道的有效阻滞剂，而且还是有效的免疫调节剂。但是，它缺乏对KV1.3通道的选择性，从而通过与其他钾通道的相互作用来产生高毒性的高风险。我们通过使用非蛋白质加合物修饰其N末端来开发了SHK的第一代合成类似物。这些类似物在保留皮摩尔效力的同时，在其他离子通道上显示出对KV1.3的特异性，并且在不影响其他T细胞子集的情况下，它们有选择地抑制人类TEM细胞的细胞因子产生和增殖。在大鼠研究中，其中一种类似物（SHK-186）抑制了发炎组织中的TEM细胞增大和运动性，抑制了延迟型超敏反应，并有效地治疗了慢性降低的实验性自身免疫性脑脊髓炎（CR-EAE； CR-EAE； MS的模型）和Pristane诱导的炎症。尽管SHK-186和相关类似物在大鼠中具有出色的安全性，并且不会损害对病毒（流感）或细菌（衣原体）病原体急性感染的保护性免疫反应，但它们受到了几种限制：（i）它们对pH和温度的变化敏感； （ii）它们的体内半衰期很短； （iii）SHK-186上的磷酸化残基可以被剥落； （iv）它们包含易于氧化的MET残留物； （v）它们的非蛋白质加合物具有免疫原性。现在，我们建议设计，生成和评估SHK的新型类似物。在特定目标1下，我们将使用分子建模和高分辨率NMR来确定KV1.3上SHK类似物的对接配置，从而设计和合成更有效和选择性的N-和C末端扩展的SHK模拟。在特定的目标2下，我们将评估SHK类似物的体外效力，选择性，稳定性以及对T淋巴细胞激活的影响，并将其质量化以增加其循环的半寿命。在特定目标3下，我们将评估用于药代动力学，免疫原性，安全性和功效的体内最有效和选择性的SHK类似物。该项目将产生KV1.3的新型肽阻滞剂，我们认为这将是为MS和其他慢性炎症性疾病开发新疗法的宝贵铅。