Claramine compounds for treating protein aggregate diseases

Description (excerpt)

CLARAMINE COMPOUNDS FOR TREATING PROTEIN AGGREGATE DISEASES [0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of U. S. Patent Application No. 63/757,916, filed February 13, 2025, which is herein incorporated by reference in its entirety. [0003] ACKNOWLEDGEMENT OF GOVERNMENT SUPPORT [0004] This invention was made by employees of The Government of the United States, as represented by the Secretary of the Army. The Government has certain rights in the invention. [0005] BACKGROUND OF THE INVENTION [0006] 1. FIELD OF THE INVENTION [0007] The field generally relates to methods and compositions for inhibiting and/or reducing amyloid plaque formation, tau aggregation, and diseases related thereto. [0008] 2. DESCRIPTION OF THE RELATED ART [0009] About two thirds of the approximately 55 million people worldwide living with dementia suffer from Alzheimer’s disease (AD), a neurodegenerative disorder caused by the deposition of misfolded proteins in the brain. In AD, the tau protein aggregates into hyperphosphorylated neurofibrillary tangles within neurons, and the amyloid-P peptide (AP) accumulates into amyloid plaques in the extracellular space of the brain parenchyma. In both cases, normally soluble monomeric Ap and tau misfold and self-associate to form large aggregates named amyloid fibrils. These highly ordered structures exhibit a signature cross-P core comprised of layers of hydrogen bonds between adjacent P-sheets down the long axis of the fibril, making these structures remarkably stable. Many amyloid fibrils, including those of tau, Ap, a-synuclein, and several others, have well-characterized autocatalytic properties, where fibril surfaces can promote the conversion of monomers to form new oligomers, some of which elongate to form new fibrils. This results in the establishment of a positive feedback loop and rationalizes the progressively increasing rate of protein deposition over the course of AD. [0010] Studies on kinetics have shown that Ap monomers initially interact with each other in a process called primary nucleation to form oligomeric assemblies. These assemblies then grow into amyloid fibrils by adding more Ap monomers to their ends, a process known as elongation. The amyloid fibrils, in turn, serve as catalytic surfaces for the formation of new oligomeric assemblies, a process known as secondary nucleation, which is the primary mechanism for the proliferation of Ap aggregates. An alternative pathwayto amyloid formation is the condensation pathway, in which a protein undergoes a liquidliquid phase separation process before aggregating into amyloid fibrils. During this process, a homogeneous liquid phase separates into two coexisting liquid phases of different densities. The high-density phase accelerates nucleation processes, which are highly concentration dependent, leading to the rapid formation of amyloid aggregates. This condensation pathway to aggregation has been observed in proteins associated with neurodegenerative diseases, such as a-synuclein, tau, and FUS (fused in sarcoma). The relevance of phase separation in the onset and progression of Alzheimer’s and other neurodegenerative diseases is unclear, as many studies use artificial additives like PEG to induce phase separation in vitro. [0011] Some aminosterols have been found to exhibit anti-amyloid properties that make them potential treatments for AD, Parkinson’s disease (PD), and potentially other disorders related to proteotoxicity. The two most studied aminosterols, originally isolated from the gastrointestinal tract of dogfish sharks, are squalamine and trodusquemine. These molecules are bile salts with a cholestane-like steroid ring, with hydroxyl and sulfate groups at C-7 and C-24, respectively, coupled to a polyamine moiety at C-3 (3beta,5alpha,7alpha,24S). Squalamine and trodusquemine have been found to effectively inhibit the aggregation, fibril formation, and toxicity of a-synuclein (which is central to the onset and development of PD) by inhibiting the binding and toxicity of stabilized soluble oligomeric aggregates of a-synuclein to cell membranes. Squalamine and trodusquemine have been found to neutralize the toxicity of stabilized oligomeric soluble aggregates of the 40-residue form of A|3 (A[34O), A[342, and the model E. coli protein HypF-N, through the unified generic mechanism of preventing or displacing the binding of cytotoxic aggregates of misfolded proteins from cell membranes. [0012] The aminosterols studied to date possess relevant anti-aggregation properties for several amyloidogenic proteins. Squalamine and trodusquemine, in particular, are potent inhibitors of a-synuclein aggregation and toxicity. Both squalamine and trodusquemine prevent the binding to cell membranes and resulting toxicity of a variety of protein misfolded oligomers, to include those of a-synuclein, A[34O, A[342, and HypF-N. Detailed structural studies on trodusquemine showed it readily inserts into model neuronal membranes and the plasma membranes of SH-SY5Y cells, and it can modulate the physical states of lipi