New strategy for the development of drugs to treat serpinopathies based on structural biology

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The serpinopathies resulting from serpin polymerization include dementia and cirrhosis. Since 2008, the target molecule for the development of the therapeutic agents has changed from the native protein to folding intermediates. In this study, we found three seed compounds for a cure of serpinopathies based on the data obtained by mapping of a refolding intermediate of neuroserpin, analysis of elongation and domain-swapping mechanisms of polymers of neuroserpin and ovalbumin, and a crystal structure of the cleaved form of the pathogenic mutant Ser49Pro of neuroserpin.