Peptide Brush Polymers: Theory and Synthesis for Functional Design

肽刷聚合物：功能设计的理论与合成

• 批准号: 2004899
• 负责人: Nathan Gianneschi
• 金额: $ 52.5万
• 依托单位: Northwestern University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2004899&HistoricalAwards=false
• 关键词: Peptide; Brush; Polymers; Theory; Synthesis

Nontechnical Summary This award by the Biomaterials program in the Division of Materials Research to Northwestern University is for the development of an approach to make peptide biomaterials into therapeutics and tools for discovery in biology. Peptides are typically small biomolecules discovered as fragments of proteins or coming from natural sources such as hormones. They are a class of molecule used to treat diseases such as diabetes. However, widespread use across diverse diseases has been severely limited compared to how many peptides are known. The promise of peptide biomaterials has also been limited because of several conspiring attributes. One is that, in using these molecules we are trying to make functional therapeutics out of that which we normally regard as food. Natural digestion processes break down peptides to amino acids before they can function. In addition, cells and tissues have physical barriers that prevent most foreign peptides from entering; an evolutionary feature that usually serves us well. These processes mean that peptides are short lived when given intravenously or orally as medicines. In addition, unlike large proteins such as antibodies, individual peptides lack the ability to make multiple contacts with target receptors that may be present on cells or invading pathogens. This is analogous to the difference between picking up a pen with one finger versus using an entire hand. We term this multivalency in target binding. This award focuses on the experimental and theoretical development of a new kind of peptide biomaterial formulation. These formulations display peptides at exceptionally high-density, enabling resistance to degradation, while maintaining and enhancing cell uptake and receptor binding, or gripping strength by multivalency. Through this effort to impact scientific problems of urgency and relevance to society, the award will establish a research internship for underrepresented post-baccalaureate students in science, to recruit them to STEM fields. The award will also enable outreach programs including one focused on clinicians interested in learning about future technologies of potential translational relevance arising from the fields of polymer chemistry and nanoscience.Technical Summary: Peptides show tremendous potential as therapeutics and as tools in chemical biology. However, this promise has been consistently compromised by natural digestion processes and by chemical and physical barriers in cells and tissues. These processes mean that peptides suffer from short half-lives upon systemic (intravenous or oral) administration and are degraded or excluded entirely from cells and organs. In addition, they can be low molecular weight as individual strands, a feature contributing to rapid clearance when administered systemically and to a lack of multivalency in target binding. This award focuses on the experimental and theoretical development of polymer scaffolds that are capable of displaying peptides at exceptionally high density enabling resistance to degradation, while maintaining and enhancing cell uptake and bioactivity. Furthermore, the project offers opportunities for broader societal impact. This is based on the fact that peptides are exciting targets, ripe for development with new delivery methods for longstanding, and for emerging diseases alike. To fuel these scientific thrusts, the program has established a research internship for underrepresented post-baccalaureate students in science to prepare them to apply for graduate school. The multidisciplinary research program seeks to broaden the base of students coming into STEM fields by recruiting them to work on scientific problems of urgency and relevance to society.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该奖项由西北大学材料研究部的生物材料计划颁发，以表彰一种将多肽生物材料转化为疗法和生物学发现工具的方法的开发。多肽通常是作为蛋白质片段被发现的小生物分子，或者来自自然来源，如激素。它们是一类用于治疗糖尿病等疾病的分子。然而，与已知的多肽数量相比，在各种疾病中的广泛使用受到了严重限制。多肽生物材料的前景也因为几个共谋属性而受到限制。一个是，在使用这些分子时，我们试图从我们通常认为是食物的东西中制造出功能疗法。自然的消化过程将多肽分解成氨基酸，然后才能发挥作用。此外，细胞和组织有物理屏障，阻止大多数外来多肽进入；这一进化特征通常对我们很有用。这些过程意味着，当通过静脉或口服给药时，多肽的寿命很短。此外，与抗体等大型蛋白质不同，单个多肽缺乏与可能存在于细胞或入侵病原体上的目标受体进行多次接触的能力。这类似于用一根手指拿起一支笔和用一只手拿起一只手的区别。我们将这种多价性称为靶标结合。该奖项侧重于一种新型多肽生物材料配方的实验和理论开发。这些制剂以极高的密度展示多肽，能够抵抗降解，同时保持和增强细胞摄取和受体结合，或通过多价态保持和增强抓握力。通过这一努力来影响对社会具有紧迫性和相关性的科学问题，该奖项将为科学方面代表性不足的毕业后学生设立一个研究实习机会，以招募他们进入STEM领域。该奖项还将推动推广计划，其中一个计划侧重于临床医生，他们有兴趣学习聚合物化学和纳米科学领域产生的潜在翻译相关性的未来技术。技术摘要：多肽显示出作为治疗和化学生物学工具的巨大潜力。然而，这一承诺一直受到自然消化过程以及细胞和组织中化学和物理障碍的影响。这些过程意味着多肽在全身(静脉或口服)给药时半衰期很短，并被降解或完全从细胞和器官中排除。此外，它们可以是低分子量的单链，这一特点有助于系统给药时快速清除，并导致靶标结合缺乏多价性。该奖项侧重于聚合物支架的实验和理论开发，这种支架能够以极高的密度展示多肽，从而能够抵抗降解，同时保持和增强细胞摄取和生物活性。此外，该项目还提供了产生更广泛社会影响的机会。这是基于这样一个事实，即多肽是令人兴奋的目标，对于长期存在的和新出现的疾病来说，开发新的递送方法的时机已经成熟。为了推动这些科学努力，该项目为理科毕业后代表性不足的学生设立了一个研究实习机会，为他们申请研究生院做准备。多学科研究计划旨在通过招募学生从事与社会相关的紧迫科学问题来扩大进入STEM领域的学生基础。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。