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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要长期目标是了解一类新型环状（大环）化合物的化学性质分子以及这些分子在调节蛋白质之间的相互作用方面可能具有的潜力。控制蛋白质-蛋白质相互作用是一个尚未充分探索的研究领域，也是研究的沃土。新药先导物和策略的发现。学术实验室、生物技术公司和大型制药公司正在投资增加对这些追求的精力。制备环是一项合成挑战，很少有通用的解决方案。也就是说，虽然许多方法已成功使用，但它们的范围或底物特异性可能受到限制。动态的共价化学是传统合成的有力替代方案，但通常，结果是混合物的产品。幸运的是，人们发现简单的化学反应可以通过两步自发地制造分子二聚化以定量产率产生单一大环产物。这些分子的主干提供了大量的操纵站点。可能影响大环选择性和亲和力的基团可以掺入蛋白质靶标，并且可以改变环的大小。拟议的努力集中于三个总体目标。前两个目标是化学的。建立了上一时期主题的一般性、替换对形状的影响、关键元素药物设计，将被探讨。形状影响亲和力、溶解度和 logP 等重要参数预测分子是否跨膜。当前的研究扩展到更大的环，采用类似蛋白质的形状（β-折叠）。这些工作将在 PI 的实验室中主要使用本科生。第三个目标是生物学的。我的合作者致力于乳腺癌研究。蛋白质-蛋白质使用截断模型探索 BRCA1 和 PALB2（乳腺癌基因产物）之间的相互作用概括了本机系统。所提出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。