Disrupting Protein-Protein Interactions with Self-Assembling Macrocycles

用自组装大环化合物破坏蛋白质-蛋白质相互作用

• 批准号: 10796097
• 负责人: ERIC E SIMANEK
• 金额: $ 33.66万
• 依托单位: TEXAS CHRISTIAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10796097
• 关键词: Adopted; Affect; Affinity; Algorithms; Alkylation; Amides; Architecture; Area; Articulation; BRCA1 gene; Behavior; Biological; Biological Models; Biophysics; Biotechnology; Breast Cancer gene; Chemical Dynamics; Chemicals; Chemistry; Collaborations; Communities; Consensus; Cyclosporins; Dimerization; Disease; Disparity; Drug Design; Elements; Etiology; Family; Geometry; Goals; Hydrazones; Hydrogen; Hydrogen Bonding; Investments; Learning; Libraries; Ligands; Membrane; Methods; Methylation; Modeling; Molecular; Molecular Conformation; Octanols; Oral; PALB2 gene; Partition Coefficient; Peptides; Periodicity; Pharmaceutical Preparations; Property; Protein Chemistry; Proteins; Protons; Reaction; Research; Shapes; Site; Solubility; Solvents; Sorting; Structure; Substrate Specificity; Surface; System; Temperature; Triazines; Vancomycin; Vertebral column; Water; Work; beta pleated sheet; bioactive natural products; design; dimer; drug discovery; flexibility; gene product; insight; interest; malignant breast neoplasm; molecular dynamics; monomer; novel; novel therapeutics; peptidomimetics; protein protein interaction; protein structure; self assembly; small molecule; tool; undergraduate student

PROJECT SUMMARY The long-term objective is to understand the chemistry of a new class of ring-shaped (macrocyclic) molecules and the potential that these molecules might have in modulating interactions between proteins. Controlling protein-protein interactions is an under-explored area of research and is fertile ground for the discovery of new drug leads and strategies. Academic labs, biotech companies and big pharma are investing increasing energies into these pursuits. Preparing rings represents a synthetic challenge that rarely has a general solution. That is, while many methods have been used successfully, they can be limited in scope or substrate specificity. Dynamic covalent chemistry is a powerful alternative to traditional synthesis, but commonly, the result is a mixture of products. Fortuitously, simple chemistries have been discovered to make molecules in 2 steps that spontaneously dimerize to yield a single macrocyclic product in quantitative yield. The backbone of these molecules offers numerous sites for manipulation. Groups that could affect selectivity and affinity of the macrocycle toward a protein target can be incorporated and the size of the ring can be changed. The proposed efforts focus on three general aims. The first two aims are chemical. Having established the generality of the motif over the last period, the affect that substitution has on shape, the critical element of drug design, will be probed. Shape influences affinity, solubility and important parameters like logP which predicts whether a molecule crosses membranes. The current studies are extended to larger rings that adopt protein-like shapes (beta-sheets). These efforts will be executed in the lab of the PI using primarily undergraduates. The third aim is biological. The collaborating co-I works on breast cancer. Protein-protein interactions between BRCA1 and PALB2 (breast cancer gene products) are explored with truncated models that recapitulate the native system. The ability of the proposed macrocycles to modulate interactions between these proteins will be assessed.

项目摘要 长期目标是了解一类新的环状（大环） 分子和这些分子可能在调节蛋白质之间的相互作用的潜力。 控制蛋白质-蛋白质相互作用是一个未被探索的研究领域，并且是研究蛋白质相互作用的肥沃土壤。 发现新的药物线索和策略。学术实验室、生物技术公司和大型制药公司都在投资 增加这些追求的能量。 制备环是一项合成挑战，很少有通用的解决方案。也就是说，虽然许多 方法已经成功地使用，但它们可能在范围或底物特异性方面受到限制。动态 共价化学是传统合成的一种强有力的替代方法，但通常，结果是混合物 的产品。 幸运的是，简单的化学方法已经被发现，使分子在两个步骤，自发地 二聚以定量产率产生单一大环产物。这些分子的骨架 提供了许多操纵的场所。可能影响大环选择性和亲和力的基团 可以结合朝向蛋白质靶的环，并且可以改变环的尺寸。 拟议的努力侧重于三个总目标。前两个目标是化学的。在建立了 最后一个时期主题的普遍性，替代对形状的影响， 药物设计，将被探索。形状影响亲和力、溶解度和重要参数，如logP， 预测一个分子是否穿过细胞膜。目前的研究扩展到更大的环， 蛋白质样形状（β-片层）。这些工作将在PI的实验室中执行，主要使用 本科生第三个目标是生物学。合作的co-I致力于乳腺癌。蛋白质 BRCA 1和PALB 2（乳腺癌基因产物）之间的相互作用用截短模型进行了研究 重现了原生系统拟议的大环化合物调节相互作用的能力 将评估这些蛋白质之间的关系。