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

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

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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.

项目摘要长期目标是了解新的环形形状（大环）的化学反应分子和这些分子在调节蛋白质之间相互作用时具有的潜力。控制蛋白质 - 蛋白质相互作用是研究不足的领域，并且是肥沃的基础发现新药铅和策略。学术实验室，生物技术公司和大型制药公司正在投资将能量增加到这些追求中。制备环代表了很少有一般解决方案的合成挑战。那就是，虽然很多方法已成功使用，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品，但通常是结果是混合物产品。幸运的是，已经发现了简单的化学作品以2步自发地制作分子二聚体以定量产量产生单个大环产物。这些分子的骨干提供许多操纵站点。可能影响大环的选择性和亲和力的组朝向蛋白质靶标可以合并，可以更改环的大小。拟议的努力集中在三个一般目标上。前两个目标是化学的。建立了在最后一个时期，主题的一般性，替代对形状的影响，是关键要素药物设计将进行探测。形状会影响亲和力，溶解度和重要参数，例如logp 预测分子是否越过膜。当前的研究扩展到采用的较大环蛋白质状形状（β片）。这些努力将主要使用PI实验室执行本科生。第三个目标是生物学。合作的共同体在乳腺癌方面工作。蛋白质蛋白质通过截短的模型探索了BRCA1和PALB2（乳腺癌基因产物）之间的相互作用这概括了天然系统。提议的大环调节相互作用的能力这些蛋白质之间将进行评估。