Lysine-Targeting Inhibitors of Amyloidogenic Protein Aggregation: A Promise for Neurodegenerative Proteinopathies

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Abstract
Inhibition of amyloidogenic-protein oligomeriza- tion and aggregation is a promising therapy-development strategy for proteinopathies, such as Alzheimer’s and Parkinson’s diseases, in which proteins self-associate into a variety of abnormal, toxic assemblies. Despite discovery of numerous compounds modulating the self-assembly process in vitro, few have reached advanced clinical trials, and none have translated into effective therapy to date. A potential reason is a lack of clear mechanistic under- standing of the interaction between the inhibitors/modulators and the target metastable protein assemblies. A unique class of compounds targets specifically Lys residues, which have been shown to be important mediators of many amyloidogenic-protein aberrant self-assembly processes due to their participation in both electrostatic and hydrophobic interactions. Although seemingly paradoxical, as these compounds do not target a specific protein, compounds targeting Lys show a remarkable ability to selectively disrupt the interactions mediating abnormal protein self-assembly. Such compounds include covalent and noncovalent Lys-binding small molecules, as well as agents controlling Lys-post-translational modification (PTM). Recent advances in this area show that the application of Lys-targeting inhibitors in antiamyloid drug discovery campaigns and Lys-reactive rational-design approaches have led to intriguing results in multiple systems, including animal models of various proteinopathies. As this strategy is applicable and promising for targeting most of the proteins involved in proteinopathies, including amyloid β -protein, tau, and α -synuclein, here we highlight Lys-binding inhibitors of abnormal protein self-assembly leading to preclinical therapeutic applications for the central nervous system.
Funding Information
  • National Institute of Neurological Disorders and Stroke (R21NS130326 to G.B., RF1NS126406 to G.B.)
  • Japan Society for the Promotion of Science (16H06194 and 24KK0115 to K.Mu., 20KK0126 and 23H03852 to K.Mu and K.Mi)
  • the Stretch Goals Fund (G.B.)

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