Synthesis and screening of DNA-encoded Libraries of Non-Peptidic Macrocycles

非肽大环化合物 DNA 编码文库的合成和筛选

• 批准号: 10323626
• 负责人: Eric Koesema
• 金额: $ 73.4万
• 依托单位: DELUGE BIOTECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323626
• 关键词: Active Sites; Address; Affinity; Aldehydes; Amides; Amines; Area; Biotechnology; Cells; Characteristics; Chemicals; Chemistry; Collection; Communicable Diseases; Complex; DNA; Development; Disease; Diversity Library; Drug Targeting; Enzymes; Explosion; Generations; Human; Immunoglobulin G; Industry; Knowledge; Lead; Libraries; Ligands; Malignant Neoplasms; Medical; Methods; Modeling; Nucleic Acids; Peptides; Permeability; Pharmaceutical Preparations; Phase; Plant Resins; Play; Positioning Attribute; Proteins; Proteome; Publications; Reaction; Research Contracts; Role; Solvents; Source; Streptavidin; Structure; Surface; TP53 gene; Testing; Therapeutic; Work; analog; design; drug quality; inhibitor/antagonist; innovation; novel; pathogen; protein protein interaction; scaffold; screening; success; thioether; transcription factor

Project Summary Most drugs target proteins with relatively deep pockets, such as enzyme active sites. However, screening collections comprised of these traditional Rule of 5-compliant molecules have consistently failed to provide high quality drug leads for many targets that function via protein-nucleic acid and protein-protein interactions (PPIs). These are the “difficult” or “undruggable” protein targets, which by some estimates comprise up to 85% of the human proteome. The importance of these types of PPIs has been well noted in cancer therapeutics and more recently in the infectious diseases field where PPIs play a role in the interaction between host and pathogen. Macrocyclic peptides (MPs) are capable of engaging these shallow, solvent exposed surfaces, but most MPs are not cell permeable. This highlights the critical need for the development of libraries of novel, cell permeable compounds capable of engaging PPI surfaces. In Phase I, we successfully demonstrated the feasibility of generating and screening large DNA-encoded libraries of non-peptidic macrocycles, which have the appropriate characteristics to address this need. In this Phase II project, we will expand the chemical diversity of these libraries, test them against several difficult targets, and establish methods to evolve primary screening hits derived from the libraries into high-quality drug leads.

项目概要 大多数药物靶向具有相对较深口袋的蛋白质，例如酶活性位点。然而，筛选 由这些传统的符合 5 规则的分子组成的集合一直未能提供高 许多通过蛋白质-核酸和蛋白质-蛋白质相互作用 (PPI) 发挥作用的靶点的优质药物先导。 这些是“困难”或“不可成药”的蛋白质靶点，据估计，它们占了 85% 的蛋白质靶点。 人类蛋白质组。这些类型的 PPI 的重要性在癌症治疗等领域已得到充分关注 最近在传染病领域，质子泵抑制剂在宿主和病原体之间的相互作用中发挥作用。 大环肽 (MP) 能够作用于这些浅的、暴露于溶剂的表面，但大多数 MP 都 不具有细胞渗透性。这凸显了开发新型、细胞渗透性的文库的迫切需要 能够接合 PPI 表面的化合物。在第一阶段，我们成功论证了可行性 生成和筛选非肽大环化合物的大型 DNA 编码文库，该文库具有适当的 的特性来满足这种需求。在这个二期项目中，我们将扩大这些物质的化学多样性 文库，针对几个困难的目标对其进行测试，并建立开发初级筛选命中的方法 从库中提取出高质量的先导药物。