Role of disulfide bridges in the folding of conotoxins

二硫键在芋螺毒素折叠中的作用

• 批准号: 8019217
• 负责人: BALAZS HARGITTAI
• 金额: $ 1.27万
• 依托单位: SAINT FRANCIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-05 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019217
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Affinity; Amides; Amino Acid Sequence; Amino Acids; Area; Arts; Basic Amino Acids; Behavior; Biologic Characteristic; Biological; Charge; Cholinergic Receptors; Code; Computer Simulation; Conotoxin; Cysteine; Diagnostic; Disulfides; Ethers; Evaluation; Exhibits; FDA approved; Family; Family member; Goals; Homocysteine; Homocystine; Homologous Gene; Housing; Ion Channel; Isomerism; Lactams; Lactones; Lead; Location; Malignant Neoplasms; Marines; Medicine; Methods; Modeling; Modification; Molecular; Molecular Conformation; Molecular Models; Muscle Rigidity; Nature; Nervous system structure; Neurons; Outcome; Parents; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Positioning Attribute; Process; Proline; Property; Proteins; Reaction; Relative (related person); Role; Scientist; Side; Solutions; Structure; Sulfur; Therapeutic; Variant; Vertebral column; Work; analog; chemical synthesis; chronic pain; conotoxin GI; conotoxin SI; design; drug development; experience; molecular dynamics; molecular modeling; novel; protein aminoacid sequence; protein folding; receptor; thioether; tool

DESCRIPTION (provided by applicant): Conotoxins are small, disulfide-rich peptides having the ability to differentiate between various types of ion channels, making them ideal diagnostic tools in the characterization of neuronal pathways and in drug development. One member of this family, ?-conotoxin MVIIA (Ziconitide) was recently approved by the FDA for the treatment of chronic pain. Evaluation of the role of disulfide bridges is essential in our understanding of protein folding. This proposal will explore how slight changes (introducing conformational restrictions or altering the size of the intramolecular bridges) in the sequences of small peptides affect folding properties. The target peptides are a-conotoxins and their analogues; thirteen or fourteen amino acid-containing peptide amides having four cysteine residues. The four cysteines can form two disulfide bridges, leading to three possible regioisomers, only one of which is found in nature. The amino acid proline's cyclic nature may impose steric constraints for the folding of the peptides, resulting in much better selectivity for the synthesis of the target native regioisomers. The work will focus in three areas: (i) Study of the variation in folding due to changes in the amino acid sequence and synthesis and biophysical characterization of conotoxins that contain a novel amino acid, proline-like with a basic side chain, which has been proven to be essential for increased biological activity. (ii) Synthesis and biophysical characterization of structures with homologues of cysteine or with a lactam bridge. And (iii) modeling (molecular dynamics and ab initio) of the molecular parameters, (S?S distance, rotational conformation of the side chains), relevant to activation energy of the bond formation that results in a specific regioisomer. Conotoxins are small peptides having the ability to differentiate between various types of ion channels, making them ideal diagnostic tools in the characterization of nervous system pathways and in drug development. For instance, Ziconitide (?-conotoxin MVIIA) has already been approved by the FDA for cancer and AIDS patients for the treatment of chronic pain. This proposal aims to develop methods to make contoxins more efficiently.

描述（由申请人提供）：结合毒素是二硫键富含二硫键的小肽，具有区分各种类型的离子通道的能力，使其成为神经元途径和药物开发中表征的理想诊断工具。 FDA最近批准了这个家族的一名？ - 抗毒素MVIIA（Ziconitide）用于治疗慢性疼痛。评估二硫键桥的作用对于我们对蛋白质折叠的理解至关重要。该建议将探讨小肽序列中的微小变化（引入构象限制或改变分子内桥的大小）会影响折叠特性。靶肽是A-抗毒素及其类似物。 13或14个含有四个半胱氨酸残基的含氨基酸的肽酰胺。这四个半胱氨酸可以形成两个二硫键，导致三个可能的区域异构体，其中只有一个在自然界中。氨基酸脯氨酸的环状性质可能会对肽的折叠施加空间约束，从而更好地选择了靶标天然区域异构体的选择性。这项工作将集中在三个领域：（i）研究由于氨基酸序列的变化，合成的变化以及含有新型氨基酸的蛋白毒素的变化以及基本侧链的脯氨酸样的综合毒素，这对于增加生物学活性是必不可少的。 （ii）与半胱氨酸的同源物或lactam桥的结构合成和生物物理表征。 （iii）分子参数的建模（分子动力学和AB始于）（S距离，侧链的旋转构象），与键形成的激活能有关，从而导致特定区域异构体。结合毒素是小肽，具有区分各种类型的离子通道的能力，使其成为神经系统途径和药物发育的理想诊断工具。例如，FDA已批准Ziconitide（？ - conotoxin MVIIA）治疗慢性疼痛的患者。该提案旨在开发方法以更有效地使二氧蛋白。