Protein-protein interactions (PPIs) are key regulators of various cellular processes. Modulating PPIs with small molecules has gained increasing attention in drug discovery, particularly targeting the 14-3-3 protein family, which interacts with several hundred client proteins and plays a central role in cellular networks. However, targeting a specific PPI of the hub protein 14-3-3, with its plethora of potential client proteins, poses a significant selectivity challenge. This not only involves the selectivity of 14-3-3 PPIs with other client proteins, but also the selective stabilization of a specific 14-3-3 binding site within a protein partner featuring several binding sites. The interaction of 14-3-3 with Tau, characterized by different phospho-site driven binding modes, forms a valuable, disease-relevant, 14-3-3 multivalent model PPI to explore this selectivity issue. This work presents the identification and early-stage optimization of small molecule fragment-like stabilizers for a specific binding site of the 14-3-3/Tau PPI. Using different biophysical assays, the stabilizing potency of the imine-bond forming molecules was mapped and X-ray crystallography studies provided structural data on the binding mode of the ternary complexes. Exploiting the unique topologies and functionalities of the different binding sites enabled the engineering of selectivity for this initial molecular glue matter for the pS214 binding site, over a second 14-3-3 binding site in Tau (pS324). These reversible covalent tool compounds will allow for the further exploration of the role of 14-3-3 in Tau aggregation.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter, @covalentmod@mstdn.science on Mastodon, and @covalentmod.bsky.social on BlueSky
Monday, February 10, 2025
Site-Specific Molecular Glues for the 14-3-3/Tau pS214 ProteinProtein Interaction via Reversible Covalent Imine Tethering
Research progress on covalent inhibitors targeting alkaline amino acids
Bing Zhao, Sha Xu, Shiqing Zhou, Xiangru Jiang, Ailin Jiang, Hongrui Lei, Xin Zhai Bioorganic Chemistry, 163, 2025, 108800, https://doi.org...
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Design, synthesis and biological evaluation of the activity-based probes for FGFR covalent inhibitorDandan Zhu, Zijian Zheng, Huixin Huang, Xiaojuan Chen, Shuhong Zhang, Zhuchu Chen, Ting Liu, Guangyu Xu, Ying Fu, Yongheng Chen, European Jo...
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DOI Ansgar Oberheide, Maxime van den Oetelaar, Jakob Scheele, Jan Borggräfe, Semmy Engelen, Michael Sattler, Christian Ottmann, ...
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Yoav Shamir, Nir London bioRxiv 2025.03.19.642201 doi: https://doi.org/10.1101/2025.03.19.642201 Recent years have seen an explosion in the...