Next-generation PEGylation: antifouling and immunoevasive semi-randomized zwitterionic peptides

非技术概述：该项目将探索使用计算机设计的多肽来增强药物输送系统，与NSF的使命保持一致，以促进科学进步和促进国家健康繁荣和福利。纳米粒子具有巨大的潜力，可以将新的、非常有希望的治疗药物输送到人体的特定位置，增强药物效力，并减少副作用。然而，血液蛋白会吸附到纳米颗粒上，导致清除。蛋白质吸附降低了纳米颗粒到达组织靶点、器官和肿瘤的能力。现有的控制纳米蛋白质吸附的材料数量有限。此外，它们与反复暴露后的过敏样免疫系统反应有关，这一点最近在针对COVID19的mRNA疫苗中得到了强调。该项目探索具有部分随机化序列的计算设计的多肽，以制造一类新的多样化的抗蛋白质吸附选项，通过随机设计，将避免过敏反应和其他长期的免疫副作用。这些材料有望成为多纳米颗粒系统的通用材料，并将改善药物输送。研究活动将与罗切斯特正在进行的K-12教育和推广工作相结合，包括“教师教学”计划和研究生/本科生研究人员指导。技术摘要：纳米粒(NP)药物递送系统(DDS)的非特异性蛋白质吸附通过减少靶组织堆积和NP递送功能并增加单核吞噬细胞系统(MPS)中的靶外堆积，挑战了NP疗法的巨大前景。目前用于对抗蛋白质吸附的防污染材料，如聚乙二醇，化学多样性有限，最近已被证明具有抗原性，COVID19的聚乙二醇化信使核糖核酸疫苗方法的不良反应突出了这一点。该项目旨在开发具有半随机序列的计算机设计的防污两性多肽(ZIP)，以创建一种多样化的新型抗污材料(SrZIP)，以抵抗适应性免疫。计算设计考虑了多肽-多肽和多肽-蛋白质的相互作用，并评估了具有最低相互作用潜力的潜在ZIP，以及保持整体相互作用特征的氨基酸取代，以允许ZIP组成的半随机化以实现多样性。SrZIP将在现有的NP配方中进行测试，并直接与聚乙二醇化进行比较。通过调查设计参数、体外行为、生物分布、药代动力学和免疫原性之间的联系，该项目将进一步了解防污材料组成和临床相关的NP性能参数之间的相互作用，同时建立一个新的防污功能类别。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。

Non-Technical Summary:This project will explore the use of computationally designed peptides to enhance drug delivery systems, aligning with NSF’s mission ‘To promote the progress of science’ and ‘to advance the national health prosperity, and welfare’. Nanoparticles have tremendous potential for delivering new, highly promising therapeutics to specific locations withing the body, enhancing drug potency, and reducing side-effects. However, blood proteins adsorb to nanoparticles, resulting in clearance. Protein adsorption reduces the ability of nanoparticles to reach tissue targets organs and tumors. Existing materials to control nanoparticle protein adsorption are limited in number. Furthermore, they are implicated in allergy-like immune system responses after repeated exposures, which has been highlighted recently by the mRNA vaccines for COVID19. This project explores computationally designed peptides with partially randomized sequences to make a new class of diverse anti-protein adsorption options, which, through randomized design, will avoid allergic reactions and other long-term immunological side effects. These materials are expected to be versatile for multiple nanoparticle systems and will enable improved drug delivery. The research activities will be integrated with Rochester’s ongoing K-12 education and outreach efforts, including the “Teach for Teachers” program and graduate/undergraduate researcher mentorship.Technical Summary:Non-specific protein adsorption to nanoparticle (NP) drug delivery systems (DDS) has challenged the tremendous promise of NP therapeutics by reducing target tissue accumulation and NP delivery function and increasing off-target accumulation in the mononuclear phagocyte system (MPS). Anti-fouling materials currently used to combat protein adsorption, such as poly(ethylene glycol), have limited chemical diversity and have been recently demonstrated to be antigenic, as highlighted by adverse reactions to PEGylated mRNA vaccine approaches for COVID19. This project seeks to develop computationally designed anti-fouling zwitterionic peptides (ZIPs) with semi-randomized sequences to create a diverse new class of anti-fouling materials (srZIPs) resistant to adaptive immunity. The computational design considers peptide-peptide and peptide-protein interactions and evaluates potential ZIPs with the lowest interaction potential, as well as amino acid substitutions that maintain overall interaction character to allow semi-randomization of ZIP composition for diversity. srZIPs will be tested in existing NP formulations and compared directly to PEGylation. By investigating links between design parameters, in vitro behavior, biodistribution, pharmacokinetics, and immunogenicity, this project will further the understanding of the interplay between anti-fouling material composition and clinically relevant NP performance parameters while establishing a new category of anti-fouling functionalities.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.