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.

项目总结