Development of Polydepsipeptides as Biomimetic Materials

聚缩酚肽仿生材料的开发

• 批准号: 8045890
• 负责人: Laura J Suggs
• 金额: $ 17.96万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045890
• 关键词: Amides; Behavior; Binding; Biocompatible Materials; Biomimetic Materials; Biomimetics; Biopolymers; Cardiac; Cells; Characteristics; Charge; Chemistry; Clinical; Development; Drug Delivery Systems; Engineering; Esters; Evaluation; Exhibits; Extracellular Matrix; Family; Goals; Heart Diseases; Heparin; Heparin Binding; Injectable; Knowledge; Libraries; Methods; Molecular; Molecular Models; Molecular Structure; Nanostructures; Outcome; Peptide Synthesis; Peptides; Phase; Polyesters; Polymer Chemistry; Polymers; Process; Property; Proteins; Recovery of Function; Regenerative Medicine; S Phase; Screening procedure; Side; Signal Transduction; Solid; Solutions; Specificity; Staging; Structure; Surface; Techniques; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Translations; Virtual Library; Work; base; biodegradable polymer; cost effective; design; functional group; innovation; interest; minimally invasive; model design; molecular dynamics; molecular modeling; monomer; nanoscale; novel; polyanion; polymerization; protein aminoacid sequence; protein structure; repaired; scale up; self assembly; simulation; small molecule libraries; virtual

DESCRIPTION (provided by applicant): This proposal seeks to develop mimics of naturally occurring ECM proteins with similar biologic functionality. The peptide mimics of interest for this proposal are polydepsipeptides (PDPs), also known as polyester amides. These polymers have properties characteristic of proteins by virtue of the ability to control the chemistry of side chain substituents. The side chains can be varied among a wide range of functionalities, resulting in a family of polymers with a host of possible molecular interactions, degradation characteristics and potential bioactivities. Expected outcomes of this project are the development of degradable materials with molecular specificity. Current techniques to develop peptide mimics rely on bulk chemistry with little variability in primary sequence or surface chemistry approaches with limitations on scale-up and clinical translation. PDPs provide a unique platform with advantages of both traditional degradable polymers and engineered peptide sequences. Because PDPs can be polymerized from a large, asymmetric six- membered ring, the side chains can be varied according to the choice of starting monomer resulting in an AB-type sequence. While this does not have the complexity of an engineered peptide, it has the advantage of potential bulk synthesis. Because the resulting polymer has sequence specificity, and based on our preliminary studies, shows relevant secondary structure, we propose to evaluate PDPs that can strongly bind the naturally occurring polyanion, heparin, for participation in polyelectrolyte complexation. Overall objective: Develop a virtual and synthetic library of polydepsipeptides consisting of alternating ester and amide linkages that can exhibit biologically relevant properties through controllable secondary structure. Based on the overall objective, three specific aims are outlined below for this project. Specific Aim 1: We propose to screen side chain substituents based on molecular modeling and dynamics simulations for relevant nanoscale structures and properties to facilitate heparin complexation. Specific Aim 2: A library of cyclic precursors will be fabricated using solid phase techniques for subsequent ring-opening polymerization and evaluation of secondary structure. Specific Aim 3: Candidate polydepsipeptides will be polymerized and evaluated for their ability to undergo polyelectrolyte complexation with heparin. We propose that alternating hydrophobic and charged functional groups will provide the appropriate nanoscale structure for assembly. PUBLIC HEALTH RELEVANCE: The overarching goal of this project is to transform the design of polymer-based therapeutics for millions who might otherwise suffer and die from heart disease. Using a rational design approach, the PI will implement a novel class of biomimetic cardiac therapeutics with the unique advantages of biologic specificity, degradability, minimally-invasive delivery, and a tailorable delivery platform. Biomaterials with nanoscale specificity have increasingly been explored for use in tissue engineering and regenerative medicine. Engineering nanostructure provides control over cell and tissue behavior that is not possible with traditional inert biomaterials. Current strategies often conform to a reductionist approach whereby natural tissue and protein structures are examined and recapitulated in a modified form. The current proposal seeks to perform a rational synthesis of materials with biologic activity based on a closed-loop approach of molecular modeling, monomer library synthesis, and subsequent testing of polymeric candidates. This type of bottom-up approach may serve as a model for the design and optimization of biomaterials with relevant bioactivity for use in cardiac therapy.

描述（由申请人提供）：该提案旨在开发具有相似生物功能的天然存在的 ECM 蛋白的模拟物。该提案感兴趣的肽模拟物是聚缩酚肽（PDP），也称为聚酯酰胺。这些聚合物由于能够控制侧链取代基的化学性质而具有蛋白质的特性。侧链可以在多种功能之间变化，从而形成一系列具有许多可能的分子相互作用、降解特性和潜在生物活性的聚合物。该项目的预期成果是开发具有分子特异性的可降解材料。 目前开发肽模拟物的技术依赖于初级序列几乎没有变化的本体化学或表面化学方法，在放大和临床转化方面受到限制。 PDP 提供了一个独特的平台，兼具传统可降解聚合物和工程肽序列的优点。由于 PDP 可以由大的不对称六元环聚合而成，因此侧链可以根据起始单体的选择而变化，从而产生 AB 型序列。虽然它不具有工程肽的复杂性，但它具有潜在的批量合成的优势。由于所得聚合物具有序列特异性，并且根据我们的初步研究，显示出相关的二级结构，因此我们建议评估能够牢固结合天然存在的聚阴离子肝素以参与聚电解质络合的PDP。总体目标：开发一个由交替的酯和酰胺键组成的虚拟合成聚缩肽库，可以通过可控的二级结构表现出生物学相关的特性。根据总体目标，该项目概述了以下三个具体目标。具体目标1：我们建议基于分子建模和动力学模拟来筛选侧链取代基，以获得相关的纳米级结构和性质，以促进肝素络合。具体目标 2：将使用固相技术构建环状前体库，用于后续的开环聚合和二级结构评估。具体目标 3：候选聚缩酚肽将被聚合并评估其与肝素进行聚电解质络合的能力。我们建议交替的疏水性和带电官能团将为组装提供适当的纳米级结构。 公共健康相关性：该项目的总体目标是为数百万人改变基于聚合物的疗法的设计，否则这些人可能会死于心脏病。 PI 将采用合理的设计方法，实施一类新型仿生心脏疗法，该疗法具有生物特异性、可降解性、微创递送和可定制的递送平台的独特优势。具有纳米级特异性的生物材料越来越多地被探索用于组织工程和再生医学。工程纳米结构提供了对细胞和组织行为的控制，这是传统惰性生物材料无法实现的。当前的策略通常符合还原论方法，即以修改的形式检查和概括自然组织和蛋白质结构。目前的提案旨在基于分子建模、单体库合成和随后的聚合物候选物测试的闭环方法，对具有生物活性的材料进行合理合成。这种自下而上的方法可以作为设计和优化具有相关生物活性的用于心脏治疗的生物材料的模型。