Development of Polydepsipeptides as Biomimetic Materials

描述（由申请人提供）：本提案旨在开发具有类似生物功能的天然存在的ECM蛋白的模拟物。该提议感兴趣的肽模拟物是聚沉积肽（pdp），也称为聚酯酰胺。由于能够控制侧链取代基的化学性质，这些聚合物具有蛋白质的特性。侧链可以在广泛的功能范围内变化，从而形成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家族。本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变化不大的散装化学或表面化学方法，在放大和临床翻译方面存在局限性。pdp提供了一个独特的平台，具有传统的可降解聚合物和工程肽序列的优点。由于pdp可以从一个大的，不对称的六元环聚合，侧链可以根据选择的起始单体而变化，从而产生ab型序列。虽然这没有工程肽的复杂性，但它具有潜在的批量合成的优势。由于所得到的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强烈结合天然存在的聚阴离子肝素参与聚电解质络合的pdp。总体目标：开发一个虚拟和合成的多肽库，由交替的酯和酰胺键组成，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，本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：将使用固相技术制备环状前体库，用于随后的开环聚合和二级结构评估。特异性目标3：候选多肽将被聚合并评估其与肝素进行多电解质络合的能力。我们提出交替的疏水和带电官能团将为组装提供合适的纳米级结构。

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.