Proximity-Induced Pharmacology for Amyloid-Related Diseases.

Proximity-induced pharmacology (PIP) for amyloid-related diseases is a cutting-edge approach to treating conditions such as Alzheimer's disease and other forms of dementia. By bringing small molecules close to amyloid-related proteins, these molecules can induce a plethora of effects that can break down pathogenic proteins and reduce the buildup of plaques. One of the most promising aspects of this drug discovery modality is that it can be used to target specific types of amyloid proteins, such as the beta-amyloid protein that is commonly associated with Alzheimer's disease. This level of specificity could allow for more targeted and effective treatments. With ongoing research and development, it is hoped that these treatments can be refined and optimized to provide even greater benefits to patients. As our understanding of the underlying mechanisms of these diseases continues to grow, proximity-induced pharmacology treatments may become an increasingly important tool in the fight against dementia and other related conditions.

Lenalidomide Stabilizes Protein-Protein Complexes by Turning Labile Intermolecular H-Bonds into Robust Interactions.

Targeted protein degradation is a promising therapeutic strategy, spearheaded by the anti-myeloma drugs lenalidomide and pomalidomide. These drugs stabilize very efficiently the complex between the E3 ligase Cereblon (CRBN) and several non-native client proteins (neo-substrates), including the transcription factors Ikaros and Aiolos and the enzyme Caseine Kinase 1α (CK1α,), resulting in their degradation. Although the structures for these complexes have been determined, there are no evident interactions that can account for the high efficiency of formation of the ternary complex. We show that lenalidomide's stabilization of the CRBN-CK1α complex is largely due to hydrophobic shielding of intermolecular hydrogen bonds. We also find a quantitative relationship between hydrogen bond robustness and binding affinities of the ternary complexes. These results pave the way to further understand cooperativity effects in drug-induced protein-protein complexes and could help in the design of improved molecular glues and more efficient protein degraders.