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• W2980451868 abstract "Clonal plasma cells in multiple myeloma and related conditions secrete immunoglobulins, including free light chains. In systemic AL amyloidosis, these light chains (LCs) or their fragments can misfold and aggregate to form insoluble, non-native amyloid fibrils that cause organ damage and eventually death. Of the 3-4,000 Americans diagnosed each year with AL amyloidosis, 1,000 will die within a year of diagnosis, mainly due to heart failure. No drugs are approved specifically for AL amyloidosis, but off-label use of cytotoxic regimens approved for multiple myeloma can be effective. However, many patients are too sick at diagnosis to tolerate chemotherapy, especially those with significant cardiomyopathy. Treatments for frail AL amyloidosis patients are therefore urgently needed. Each patient has a unique light chain sequence. Only a minority of individuals with a plasma cell dyscrasia will develop amyloidosis. We therefore investigated the differences between AL-associated and non-AL-associated LCs. Full-length LCs from AL patients are less stable than other LCs, and full-length LCs remain soluble under conditions where their isolated variable domains readily aggregate. Disruption or proteolytic removal of the constant domain appears to be necessary to allow aggregation of LCs in vitro. The earliest studies on AL amyloid suggested that the variable domain forms the core of the fibril – these results have been confirmed recently by high-resolution structures of AL amyloid fibrils extracted from patients. These data all support the hypothesis that stabilization of antibody LCs could prevent misfolding, proteolysis and aggregation of LCs in patients, and be of benefit to patients. Stopping amyloid formation at the beginning by preventing precursor protein misfolding is a proven strategy to treat transthyretin amyloidosis. We therefore aim to develop drugs that can stabilize LCs and prevent amyloid deposition. This strategy is orthogonal and complementary to existing and emerging treatments for AL amyloidosis. We have identified small molecule stabilizers of the native dimeric structure of full-length LCs. A protease-coupled fluorescence polarization-based high-throughput screen identified small molecules that stabilize LCs against unfolding and proteolysis. Structural data demonstrate that at least one class of hits bind at the LC-LC dimerization interface within full-length light chains, utilizing variable domain residues that are highly conserved in most AL patients. The small molecule stabilizers identified bind to conserved residues at the variable domain–variable domain interface in the native dimer, stabilizing this putative non-toxic structure. We aim to develop more efficacious small molecules that could become drug candidates." @default.
• W2980451868 created "2019-10-25" @default.
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• W2980451868 date "2019-10-01" @default.
• W2980451868 modified "2023-09-26" @default.
• W2980451868 title "Stabilization of amyloidogenic antibody light chains as a potential therapeutic strategy in AL amyloidosis" @default.
• W2980451868 doi "https://doi.org/10.1016/j.clml.2019.09.536" @default.
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