Reversible Dual-Covalent Molecular Locking of the 14-3-3/ERRγ Protein-Protein Interaction as a Molecular Glue Drug Discovery Approach.
Reversible Dual-Covalent Molecular Locking of the 14-3-3/ERRγ Protein-Protein Interaction as a Molecular Glue Drug Discovery Approach.
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DOI：
10.1021/jacs.2c12781
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发表时间：
2023-03-29
影响因子：
15
通讯作者：
Brunsveld, Luc
中科院分区：
文献类型：
--
作者：
Somsen, Bente A.;Schellekens, Rick J. C.;Verhoef, Carlo J. A.;Arkin, Michelle R.;Ottmann, Christian;Cossar, Peter J.;Brunsveld, Luc
稳定蛋白质 - 蛋白质相互作用（PPI）的分子作为生物物理学和（结构）生物学的工具化合物，以及分子胶药物发现的起点，具有极其重要的价值。然而，确定PPI稳定物质的初始起点极具挑战性，且化学优化工作繁重。受化学交联和基于可逆共价片段的药物发现的启发，我们开发了一种称为“分子锁”的方法，以快速获取类似分子胶的工具化合物。这些双共价小分子与每个伙伴蛋白质上的亲核氨基酸发生可逆反应，从而动态交联蛋白质复合物。枢纽蛋白14 - 3 - 3和雌激素相关受体γ（ERRγ）之间的PPI被用作一个具有药理学相关性的案例研究。基于一个有针对性的双反应小分子库，一种分子胶工具化合物得以快速开发。生化分析和X射线晶体学研究验证了通过动态共价交联形成的三元共价复合物以及整体PPI的稳定。分子锁方法对特定的14 - 3 - 3/ERRγ复合物具有高度选择性，而对其他14 - 3 - 3复合物则不然。这种选择性是由分子反应性和对复合PPI结合界面的分子识别的相互作用所驱动的。双共价锁的长寿命使得即使在存在其他几种具有更高内在结合亲和力的竞争性14 - 3 - 3作用对象时，也能选择性地稳定14 - 3 - 3/ERRγ复合物。分子锁方法能够系统地、有选择性地且有效地稳定蛋白质复合物，以支持分子胶药物发现。
Molecules that stabilize protein–protein interactions (PPIs) are invaluable as tool compounds for biophysics and (structural) biology, and as starting points for molecular glue drug discovery. However, identifying initial starting points for PPI stabilizing matter is highly challenging, and chemical optimization is labor-intensive. Inspired by chemical crosslinking and reversible covalent fragment-based drug discovery, we developed an approach that we term “molecular locks” to rapidly access molecular glue-like tool compounds. These dual-covalent small molecules reversibly react with a nucleophilic amino acid on each of the partner proteins to dynamically crosslink the protein complex. The PPI between the hub protein 14-3-3 and estrogen-related receptor γ (ERRγ) was used as a pharmacologically relevant case study. Based on a focused library of dual-reactive small molecules, a molecular glue tool compound was rapidly developed. Biochemical assays and X-ray crystallographic studies validated the ternary covalent complex formation and overall PPI stabilization via dynamic covalent crosslinking. The molecular lock approach is highly selective for the specific 14-3-3/ERRγ complex, over other 14-3-3 complexes. This selectivity is driven by the interplay of molecular reactivity and molecular recognition of the composite PPI binding interface. The long lifetime of the dual-covalent locks enabled the selective stabilization of the 14-3-3/ERRγ complex even in the presence of several other competing 14-3-3 clients with higher intrinsic binding affinities. The molecular lock approach enables systematic, selective, and potent stabilization of protein complexes to support molecular glue drug discovery.
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影响因子：
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作者：
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