Discovery of 14-3-3 PPI Stabilizers by Extension of an Amidine-Substituted Thiophene Fragment.

Chembiochem

Laboratory of Chemical Biology, Department of Biomedical Engineering and, Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands.

Published: January 2024

Protein-protein interaction (PPI) modulation is a promising approach in drug discovery with the potential to expand the 'druggable' proteome and develop new therapeutic strategies. While there have been significant advancements in methodologies for developing PPI inhibitors, there is a relative scarcity of literature describing the 'bottom-up' development of PPI stabilizers (Molecular Glues). The hub protein 14-3-3 and its interactome provide an excellent platform for exploring conceptual approaches to PPI modulation, including evolution of chemical matter for Molecular Glues. In this study, we employed a fragment extension strategy to discover stabilizers for the complex of 14-3-3 protein and an Estrogen Receptor alpha-derived peptide (ERα). A focused library of analogues derived from an amidine-substituted thiophene fragment enhanced the affinity of the 14-3-3/ERα complex up to 6.2-fold. Structure-activity relationship (SAR) analysis underscored the importance of the newly added, aromatic side chain with a certain degree of rigidity. X-ray structural analysis revealed a unique intermolecular π-π stacking binding mode of the most active analogues, resulting in the simultaneous binding of two molecules to the PPI binding pocket. Notably, analogue 11 displayed selective stabilization of the 14-3-3/ERα complex.

Download full-text PDF

Source
http://dx.doi.org/10.1002/cbic.202300636DOI Listing

Publication Analysis

Top Keywords

ppi stabilizers
8
amidine-substituted thiophene
8
thiophene fragment
8
ppi modulation
8
molecular glues
8
14-3-3/erα complex
8
ppi
6
discovery 14-3-3
4
14-3-3 ppi
4
stabilizers extension
4

Similar Publications

The impact of animal-based food production on climate change drives the development of plant-based alternatives. We demonstrate the use of colloidal thermogelation on a real nanoemulsion system to create structured gels that could be of interest for thermo-mechanical processing of next-generation plant-based food applications. We use a commercial pea protein isolate (PPI) without further purification to stabilize a 20 vol% peanut oil-in-water nanoemulsion at pH = 7 by high-pressure homogenization (HPH) and demonstrate the temperature induced gelation behavior of the nanoemulsion as a function of the HPH processing parameters.

View Article and Find Full Text PDF

Engineering Air-Stable Triarylmethyl Radicals with One Pyrrole Ring.

Org Lett

January 2025

School of Chemistry, Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University, Xi'an 710049, China.

Herein, seven air-stable triarylmethyl radicals (-), each featuring a pyrrole ring, were successfully synthesized. A comprehensive investigation into the linkages at the α-, β-, and -positions of the pyrrole ring, along with various substituents, revealed that the p-π conjugation between the central radical carbon and the pyrrole ring plays a crucial role in the distribution of spin density and overall stability. Notably, radicals to displayed excellent electrochemical and photostability.

View Article and Find Full Text PDF

Pickering Emulsions Stabilized by Pea Protein Isolate-Cellulose Conjugates Prepared via the Maillard Reaction and Their Application in Active Substance Protection.

Langmuir

December 2024

Key Laboratory of Synthetic and Biological Colloids, School of Chemical and Material Engineering, Jiangnan University, 1800 Lihu Road, Wuxi 214122, Jiangsu, China.

The development of innovative solid particles from renewable resources possessing high biocompatibility and exceptional emulsification capabilities is crucial for stabilizing Pickering emulsions and advancing carrier systems. In this study, a pea protein isolate (PPI)-cellulose conjugate particle was prepared by the Maillard reaction. Compared to the isoelectric point of pH 4.

View Article and Find Full Text PDF

Phosphatases are enzymes that catalyze the hydrolysis of phosphate esters. They play critical roles in diverse biological processes such as extracellular nucleotide homeostasis, transport of molecules across membranes, intracellular signaling pathways, or vertebrate mineralization. Among them, tissue-nonspecific alkaline phosphatase (TNAP) is today increasingly studied, due to its ubiquitous expression and its ability to dephosphorylate a very broad range of substrates and participate in several different biological functions.

View Article and Find Full Text PDF

Introduction: Hyperuricemia (HUA) is a metabolic syndrome caused by purine metabolism disorders. (ZP) is a medicinal and food homologous plant, and its ripe peel is used to treat diseases and as a spice for cooking. Some studies have shown that ZP can inhibit the formation of xanthine oxidase and reduce the production of uric acid.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!