Molecular Design of Hyaluronan with Polypeptide Branches of Controlled Structure

具有受控结构的多肽分支的透明质酸的分子设计

• 批准号: 7230276
• 负责人: Jules John Magda
• 金额: $ 14.14万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230276
• 关键词: Adhesions; Amines; Amino Acids; Antigens; Antioxidants; Arthritis; Bacteria; Benign; Biocompatible Materials; Cartilage Matrix; Cereals; Charge; Chemicals; Cicatrix; Class; Comb animal structure; Condition; Connective Tissue; Degenerative polyarthritis; Development; Drug Delivery Systems; Drug Formulations; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Extracellular Matrix; Eye; Frequencies; Future; Gel; Gel Chromatography; Goals; Grant; Human; Hyaluronan; Hyaluronic Acid; Immune system; In Situ; Injectable; Lead; Length; Leucine; Life; Ligands; Liquid substance; Literature; Mass Spectrum Analysis; Measurement; Measures; Methods; Modeling; Molecular; Molecular Weight; Neutrons; Numbers; Operative Surgical Procedures; Osmotic Pressure; Pain; Peptides; Physiological; Polymers; Polysaccharides; Property; Reaction; Recombinants; Relaxation; Research; Resistance; Rheology; Saline; Serum Proteins; Shock; Signal Pathway; Source; Spectroscopy, Fourier Transform Infrared; Structure; Surface; Synovial Fluid; Techniques; Thinking; Time; Tissue Engineering; Use of New Techniques; Vertebral column; Viscosity; Work; Wound Healing; aqueous; base; clinical application; cost; design; light scattering; models and simulation; novel; physical property; polymerization; polypeptide; protein aminoacid sequence; remediation; simulation; soft tissue; viscoelasticity

DESCRIPTION (provided by applicant): Hyaluronic acid (HA) is a charged polysaccharide that is virtually "invisible" to the body's immune system because of its natural abundance in connective tissues. Recently it has become possible to synthesize long polypeptides having controlled structure and containing terminal primary amines needed for grafting reactions. It is proposed to use this new technique to conjugate long polypeptide chains to the backbones of HA molecules of high molecular weight. The novel comb-branched HA derivatives so obtained are expected to be useful as chondroprotective synovia! fluid supplements, and for use in viscosurgery and in drug delivery. The polypeptides will have a narrow chain length distribution, and will contain hydrophobic amino acids (e.g. leucine) that serf-assemble into alpha-helical domains under aqueous conditions. Due to these hydrophobic branches, the HA derivative will function as an "associative thickener" that can be used in injected formulations to boost the viscoelasticity of synovial fluid for remediation of osteoarthritis (OA) at relatively low HA content. With attached branches, shorter HA chains can be used to obtain equivalent boost in viscoelasticity, and shorter HA chains are thought to be more effective in promoting intracellular signaling pathways beneficial to OA treatment. At somewhat higher concentrations, the comb-branched HA derivative could also be used as an in situ gelling biomaterial that could be injected into the body at low viscosity, and which would self-assemble into an associative network once in place inside the body. It should be possible to tune the physical properties of these materials (gel strength, viscoelasticity, viscosity shear-thinning, osmotic pressure) by judicious choice of branch length, branch spacing, and peptide chemical identity guided by molecular simulations. In future enhancements, the long branches could be used to carry antioxidants or peptide ligands beneficial for treatment of osteoarthritis. The research proposed here may lead to the development of more potent and long-lasting injectable formulations for alleviating the pain associated with arthritis, or allow certain types of surgery to be performed with less scarring.

描述（由申请人提供）：透明质酸（HA）是一种带电多糖，由于其在结缔组织中的天然丰度，对人体免疫系统几乎是“不可见的”。最近，合成具有受控结构并含有接枝反应所需的末端伯胺的长多肽已成为可能。建议使用这种新技术将长多肽链缀合到高分子量HA分子的主链上。如此获得的新型梳状分支HA衍生物预期可用作软骨保护性滑液！流体补充剂，以及用于粘性外科手术和药物递送。多肽将具有窄链长分布，并且将含有在水性条件下自组装成α-螺旋结构域的疏水性氨基酸（例如亮氨酸）。由于这些疏水分支，HA衍生物将起到“缔合增稠剂”的作用，其可用于注射制剂中以提高滑液的粘弹性，用于在相对低的HA含量下修复骨关节炎（OA）。通过连接的分支，较短的HA链可用于获得粘弹性的等效增强，并且较短的HA链被认为在促进有益于OA治疗的细胞内信号传导途径方面更有效。在稍高的浓度下，梳状分支的HA衍生物也可以用作原位胶凝生物材料，其可以以低粘度注射到体内，并且一旦在体内就位，其将自组装成缔合网络。应该可以通过明智地选择分支长度、分支间距和由分子模拟指导的肽化学特性来调节这些材料的物理性质（凝胶强度、粘弹性、粘度剪切变稀、渗透压）。在未来的改进中，长分支可以用来携带抗氧化剂或有利于治疗骨关节炎的肽配体。 这里提出的研究可能会导致开发更有效和持久的可注射制剂，以减轻与关节炎相关的疼痛，或允许进行某些类型的手术，减少疤痕。

项目成果

Comparison of surfactants used to prepare aqueous perfluoropentane emulsions for pharmaceutical applications.

• DOI: 10.1021/la100307r
• 发表时间: 2010-04-06
• 期刊: Langmuir : the ACS journal of surfaces and colloids
• 作者: Kandadai MA;Mohan P;Lin G;Butterfield A;Skliar M;Magda JJ
• 通讯作者: Magda JJ

Structural, mechanical and osmotic properties of injectable hyaluronan-based composite hydrogels.

• DOI: 10.1016/j.polymer.2010.06.027
• 发表时间: 2010-09-03
• 期刊: POLYMER
• 影响因子: 4.6
• 作者: Horkay, Ferenc;Magda, Jules;Alcoutlabi, Mataz;Atzet, Sarah;Zarembinski, Thomas
• 通讯作者: Zarembinski, Thomas

Polypeptide grafted hyaluronan: synthesis and characterization.

• DOI: 10.1021/bm1004146
• 发表时间: 2010-09-13
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Wang, Xiaojun;Messman, Jamie;Mays, Jimmy W.;Baskaran, Durairaj
• 通讯作者: Baskaran, Durairaj

Rheological properties of cross-linked hyaluronan-gelatin hydrogels for tissue engineering.

• DOI: 10.1002/mabi.200800141
• 发表时间: 2009-01-09
• 期刊: MACROMOLECULAR BIOSCIENCE
• 影响因子: 4.6
• 作者: Vanderhooft, Janssen L.;Alcoutlabi, Mataz;Magda, Jules J.;Prestwich, Glenn D.
• 通讯作者: Prestwich, Glenn D.

Polypeptide grafted hyaluronan: A self-assembling comb-branched polymer constructed from biological components.

• DOI: 10.1016/j.eurpolymj.2011.07.017
• 发表时间: 2011-10-01
• 期刊: EUROPEAN POLYMER JOURNAL
• 影响因子: 6
• 作者: Kandadai, Madhuvanthi A.;Anumolu, Rajasekhar;Wang, Xiaojun;Baskaran, Durairaj;Pease, Leonard F., III;Bedrov, Dmitry;Smith, Grant D.;Mays, Jimmy W.;Magda, Jules J.
• 通讯作者: Magda, Jules J.