Lysosomes are the primary site for removal of old and misfolded proteins and to maintain cellular homeostasis, and positive lysosomal modulation has been shown to enhance protein clearance to protect against protein accumulation pathology. Small-molecule lysosomal modulators, for instance Z-Phe-Ala-diazomethylketone (PADK), at appropriate concentration elicit marked up-regulation of cathepsins and other lysosomal enzymes without any indications of synaptic compromise, behavioral abnormalities, or major organ malfunctions. Recent work designed and synthesized compounds with the objective to improve potency, selectivity, and metabolic stability. We utilized the PADK structure as a departure point to develop a non-peptidyl lead series. Resultant structures demonstrated that we could remove the internal amide linkage, eliminate the highly reactive diazoketone moiety, and develop highly flexible, enantioselective routes for first-in-class compounds. The lead series maintained or improved the modulatory profile of PADK, providing protection in the hippocampal slice model of protein accumulation that exhibits experimentally-induced phosphorylated tau deposits, ubiquitinated inclusions, and synaptic compromise. Results from animal studies and preliminary safety assessment will be presented. The novel compounds will be used to further design efficacious modulators, for protective agents that enhance protein clearance, promote synaptic integrity, and slow the progression of proteinopathies.
protein accumulation diseases
positive lysosomal modulation