Guaiacol as a drug candidate for treating adult polyglucosan body disease

• DOI: 10.1172/jci.insight.99694
• Publication Date: 2018-09-05T15:02:36Z
• Authors: Or Kakhlon; Igor Ferreira; Leonardo J. Solmesky; Netaly Khazanov; Alexander Lossos; Rafael Alvarez; Deniz Yetil; Sergey Pampou; Miguel Weil; Hanoch Senderowitz; Pablo Escriba; Wyatt W. Yue; H. Orhan Akman
• Keywords: Guaiacol

Adult polyglucosan body disease (APBD) is a late-onset caused by intracellular accumulation of bodies, formed due to glycogen-branching enzyme (GBE) deficiency. To find treatment for APBD, we screened 1,700 FDA-approved compounds in fibroblasts derived from APBD-modeling GBE1-knockin mice. Capitalizing on fluorescent periodic acid-Schiff reagent, which interacts with polyglucosans the cell, this screen discovered that flavoring agent guaiacol can lower polyglucosans, result also confirmed APBD patient fibroblasts. Biochemical assays showed lowers basal and glucose 6-phosphate-stimulated glycogen synthase (GYS) activity. Guaiacol increased inactivating GYS1 phosphorylation master activator catabolism, AMP-dependent protein kinase. mouse model rescued grip strength shorter lifespan. These treatments had no adverse effects except making mice slightly hyperglycemic, possibly reduced liver levels. In addition, corrected penile prolapse aged Guaiacol's curative be explained its reduction peripheral nerve, liver, heart, despite short half-life up 60 minutes most tissues. Our results form basis use as prepare clinical trials APBD.