title: AUTEN-67, an autophagy-enhancing drug candidate with potent antiaging and neuroprotective effects.
abstract: Autophagy is a major molecular mechanism that eliminates cellular damage in eukaryotic organisms. Basal levels of autophagy are required for maintaining cellular homeostasis and functioning. Defects in the autophagic process are implicated in the development of various age-dependent pathologies including cancer and neurodegenerative diseases, as well as in accelerated aging. Genetic activation of autophagy has been shown to retard the accumulation of damaged cytoplasmic constituents, delay the incidence of age-dependent diseases, and extend life span in genetic models. This implies that autophagy serves as a therapeutic target in treating such pathologies. Although several autophagy-inducing chemical agents have been identified, the majority of them operate upstream of the core autophagic process, thereby exerting undesired side effects. Here, we screened a small-molecule library for specific inhibitors of MTMR14, a myotubularin-related phosphatase antagonizing the formation of autophagic membrane structures, and isolated AUTEN-67 (autophagy enhancer-67) that significantly increases autophagic flux in cell lines and in vivo models. AUTEN-67 promotes longevity and protects neurons from undergoing stress-induced cell death. It also restores nesting behavior in a murine model of Alzheimer disease, without apparent side effects. Thus, AUTEN-67 is a potent drug candidate for treating autophagy-related diseases.
authors: a Velgene Biotechnology Research Ltd. , Szeged , Hungary.
authors: Diána
authors: D
authors: Papp
authors: a Velgene Biotechnology Research Ltd. , Szeged , Hungary.|b Department of Genetics , Eötvös Loránd University , Budapest , Hungary.
authors: Tibor
authors: T
authors: Kovács
authors: a Velgene Biotechnology Research Ltd. , Szeged , Hungary.|b Department of Genetics , Eötvös Loránd University , Budapest , Hungary.
authors: Viktor
authors: V
authors: Billes
authors: b Department of Genetics , Eötvös Loránd University , Budapest , Hungary.
authors: Máté
authors: M
authors: Varga
authors: a Velgene Biotechnology Research Ltd. , Szeged , Hungary.|b Department of Genetics , Eötvös Loránd University , Budapest , Hungary.
authors: Anna
authors: A
authors: Tarnóci
authors: c Avidin Ltd. , Szeged , Hungary.
authors: László
authors: L
authors: Hackler
authors: c Avidin Ltd. , Szeged , Hungary.|d Laboratory of Functional Genomics, Institute of Genetics, Biological Research Center , Szeged , Hungary.
authors: László G
authors: LG
authors: Puskás
authors: e Department of Physiology and Neurobiology , Eötvös Loránd University , Budapest , Hungary.
authors: Hanna
authors: H
authors: Liliom
authors: e Department of Physiology and Neurobiology , Eötvös Loránd University , Budapest , Hungary.
authors: Krisztián
authors: K
authors: Tárnok
authors: e Department of Physiology and Neurobiology , Eötvös Loránd University , Budapest , Hungary.|f MTA-ELTE NAP B Neuronal Cell Biology Research Group, Eötvös Loránd University , Budapest , Hungary.
authors: Katalin
authors: K
authors: Schlett
authors: g Institute of Enzymology, Research Center for Natural Sciences , Budapest , Hungary.
authors: Adrienn
authors: A
authors: Borsy
authors: a Velgene Biotechnology Research Ltd. , Szeged , Hungary.
authors: Zsolt
authors: Z
authors: Pádár
authors: h Department of Anatomy , Cell and Developmental Biology, Eötvös Loránd University , Budapest , Hungary.
authors: Attila L
authors: AL
authors: Kovács
authors: h Department of Anatomy , Cell and Developmental Biology, Eötvös Loránd University , Budapest , Hungary.
authors: Krisztina
authors: K
authors: Hegedűs
authors: h Department of Anatomy , Cell and Developmental Biology, Eötvös Loránd University , Budapest , Hungary.
authors: Gábor
authors: G
authors: Juhász
authors: a Velgene Biotechnology Research Ltd. , Szeged , Hungary.
authors: Marcell
authors: M
authors: Komlós
authors: a Velgene Biotechnology Research Ltd. , Szeged , Hungary.
authors: Attila
authors: A
authors: Erdős
authors: i Karolinska Institute , Department of Clinical Neuroscience , Stockholm , Sweden.|j Imperial College-NTU, Lee Kong Chian School of Medicine, Nanyang Technological University , Singapore.|k Imperial College London , Department of Medicine, Division of Brain Sciences , London , UK.
authors: Balázs
authors: B
authors: Gulyás
authors: a Velgene Biotechnology Research Ltd. , Szeged , Hungary.|b Department of Genetics , Eötvös Loránd University , Budapest , Hungary.
authors: Tibor
authors: T
authors: Vellai
mesh_terms: D000375:Aging / Q000187:drug effects*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D004331:Drosophila melanogaster / Q000187:drug effects / Q000378:metabolism; D005216:Fat Body / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008136:Longevity / Q000187:drug effects; D008297:Male; D051379:Mice; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D009425:Nesting Behavior / Q000187:drug effects; D000066829:Neuroprotection / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D015027:Zebrafish; D000096926:Benzenesulfonamides
chemical_list: D016564:Amyloid beta-Protein Precursor; D009285:Naphthoquinones; D018696:Neuroprotective Agents; D010744:Phosphoric Monoester Hydrolases; D013449:Sulfonamides; C000612165:N-(3-(benzimidazol-1-yl)-1,4-dioxonaphthalen-2-yl)-4-nitrobenzenesulfonamide; D000096926:Benzenesulfonamides; C515634:MTMR14 protein, human
keywords: AUTEN-67; EDTP; HeLa cells; LC3B-II; MTMR14/Jumpy; SQSTM1/p62; age-dependent diseases; aging; autophagy induction; drug candidate; model organism; neuroprotection