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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.

项目总结