SBIR Phase I: Development of DNA-Encoded Peptidomimetic Library for High-Affinity Binders Against Disease-Related Proteins

SBIR 第一阶段：开发 DNA 编码的拟肽文库，用于针对疾病相关蛋白的高亲和力结合剂

• 批准号: 1843405
• 负责人: Kurt Gish
• 金额: $ 22.5万
• 依托单位: TRILO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1843405&HistoricalAwards=false
• 关键词: SBIR; Phase; Development; DNA; Encoded

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project will be the development of a new class of high affinity compounds that would be small enough to be delivered into challenging environments such as living cells. Inhibitors of disease-related proteins are central to modern therapeutics across the spectrum of diseases, from cancer to autoimmune diseases, to viral infections, and even to certain hereditary disorders. Many of these drivers of disease are transcription factors or signal-transduction molecules, yet these proteins are commonly thought of as "undruggable," due to a lack of small pockets for drug binding or due to large protein-protein interaction interfaces. This proposal is aimed at developing an easily screenable library, consisting of DNA-encoded peptidomimetics, whose members have the necessary properties to inhibit these "yet-to-be-drugged" proteins. Of highest commercial importance, these compounds could address many of the currently "undruggable" molecular drivers of diseases such as cancer and autoimmune disorders.The intellectual merit of this SBIR Phase I project is to create a DNA-encoded library of constrained peptidomimetic compounds. Current DNA-encoded libraries are primarily limited to small molecules (DNA-encoded chemical libraries; DECLs) or to natural amino acids in the context of translated-protein display (e.g., phage display or mRNA display). In contrast, member molecules of this library will have a much larger binding surface than current small molecules from DECLs, and will be both protease resistant and have a wide range of chemical side chains, unlike the natural peptides from phage display. The goal of this project is to demonstrate the ability to synthesize compounds with conformational rigidity along with parallel DNA encoding. A library of these compounds could be screened to discover new therapeutic candidates (human and veterinary), life sciences research tools, and heat-resistant diagnostic reagents.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.

这个小企业创新研究（SBIR）第一阶段项目的更广泛的影响/商业潜力将是开发一类新的高亲和力化合物，这种化合物足够小，可以输送到具有挑战性的环境中，如活细胞。疾病相关蛋白的抑制剂是各种疾病的现代治疗方法的核心，从癌症到自身免疫性疾病，到病毒感染，甚至某些遗传性疾病。许多这些疾病的驱动因素是转录因子或信号转导分子，然而这些蛋白质通常被认为是“不可药物的”，因为缺乏药物结合的小口袋或由于大的蛋白质-蛋白质相互作用界面。该建议旨在开发一个易于筛选的文库，由dna编码的肽模拟物组成，其成员具有抑制这些“尚未被药物化”的蛋白质的必要特性。具有最高商业价值的是，这些化合物可以解决许多目前“无法治疗”的疾病的分子驱动因素，如癌症和自身免疫性疾病。这个SBIR一期项目的智力优势是创建一个dna编码的受限肽类化合物文库。目前的dna编码文库主要局限于小分子（dna编码的化学文库；decl）或翻译蛋白展示中的天然氨基酸（如噬菌体展示或mRNA展示）。相比之下，该文库的成员分子将比目前来自decl的小分子具有更大的结合表面，并且将具有蛋白酶抗性和广泛的化学侧链，这与来自噬菌体展示的天然肽不同。该项目的目标是证明合成具有构象刚性的化合物以及平行DNA编码的能力。这些化合物的文库可以筛选发现新的候选治疗药物（人类和兽医），生命科学研究工具和耐热诊断试剂。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。