An analog of glibenclamide selectively enhances autophagic degradation of misfolded α1-antitrypsin Z

Yan Wang, Murat C. Cobanoglu, Jie Li, Tunda Hidvegi, Pamela Hale, Michael Ewing, Andrew S. Chu, Zhenwei Gong, Radhika Muzumdar, Stephen C. Pak, Gary A. Silverman, Ivet Bahar, David H. Perlmutter

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

The classical form of α1-antitrypsin deficiency (ATD) is characterized by intracellular accumulation of the misfolded variant α1-antitrypsin Z (ATZ) and severe liver disease in some of the affected individuals. In this study, we investigated the possibility of discovering novel therapeutic agents that would reduce ATZ accumulation by interrogating a C. elegans model of ATD with high-content genome-wide RNAi screening and computational systems pharmacology strategies. The RNAi screening was utilized to identify genes that modify the intracellular accumulation of ATZ and a novel computational pipeline was developed to make high confidence predictions on repurposable drugs. This approach identified glibenclamide (GLB), a sulfonylurea drug that has been used broadly in clinical medicine as an oral hypoglycemic agent. Here we show that GLB promotes autophagic degradation of misfolded ATZ in mammalian cell line models of ATD. Furthermore, an analog of GLB reduces hepatic ATZ accumulation and hepatic fibrosis in a mouse model in vivo without affecting blood glucose or insulin levels. These results provide support for a drug discovery strategy using simple organisms as human disease models combined with genetic and computational screening methods. They also show that GLB and/or at least one of its analogs can be immediately tested to arrest the progression of human ATD liver disease.

Original languageEnglish
Article numbere0209748
JournalPloS one
Volume14
Issue number1
DOIs
StatePublished - Jan 2019

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