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.

项目摘要 大多数药物针对的是口袋相对较深的蛋白质，如酶活性部位。然而，筛查 由这些传统的5顺式规则分子组成的集合始终无法提供高 高质量的药物通过蛋白质-核酸和蛋白质-蛋白质相互作用(PPI)对许多靶点起作用。 这些都是“难以下药”或“无法下药”的蛋白质靶标，据估计，它们构成了高达85%的 人类蛋白质组。这些类型的PPI的重要性已经在癌症治疗和更多方面得到了很好的重视 近年来，在传染病领域，PPI在宿主和病原体之间的相互作用中发挥作用。 大环肽(MPS)能够与这些浅的、暴露在溶剂中的表面接触，但大多数MPS 不是细胞渗透性的。这凸显了开发新的、细胞渗透性的图书馆的迫切需要 能够与PPI表面接合的化合物。在第一阶段，我们成功地论证了 生成和筛选大型DNA编码的非肽大环文库，这些文库具有适当的 特征来满足这一需求。在这个第二阶段的项目中，我们将扩大这些化合物的化学多样性 库，针对几个困难的目标测试它们，并建立方法来进化初步筛选命中 从图书馆衍生成高质量的药物线索。