title: Small molecule enhancers of rapamycin-induced TOR inhibition promote autophagy, reduce toxicity in Huntington's disease models and enhance killing of mycobacteria by macrophages.
abstract: Upregulation of autophagy may have therapeutic benefit in a range of diseases that includes neurodegenerative conditions caused by intracytosolic aggregate-prone proteins, such as Huntington's disease, and certain infectious diseases, such as tuberculosis. The best-characterized drug that enhances autophagy is rapamycin, an inhibitor of the TOR (target of rapamycin) proteins, which are widely conserved from yeast to man. Unfortunately, the side effects of rapamycin, especially immunosuppression, preclude its use in treating certain diseases including tuberculosis, which accounts for approximately 2 million deaths worldwide each year, spurring interest in finding novel drugs that selectively enhance autophagy. We have recently reported a novel two-step screening process for the discovery of such compounds. We first identified compounds that enhance the growth-inhibitory effects of rapamycin in the budding yeast Saccharomyces cerevisiae, which we termed small molecule enhancers of rapamycin (SMERs). Next we showed that three SMERs induced autophagy independently, or downstream of mTOR, in mammalian cells, and furthermore enhanced the clearance of a mutant huntingtin fragment in Huntington's disease cell models. These SMERs also protected against mutant huntingtin fragment toxicity in Drosophila. We have subsequently tested two of the SMERs in models of tuberculosis and both enhance the killing of mycobacteria by primary human macrophages.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: R Andres
authors.initials: RA
authors.lastname: Floto
authors.forename: Sovan
authors.initials: S
authors.lastname: Sarkar
authors.forename: Ethan O
authors.initials: EO
authors.lastname: Perlstein
authors.forename: Beate
authors.initials: B
authors.lastname: Kampmann
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D004330:Drosophila / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology; D049453:Luciferases, Bacterial / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008954:Models, Biological; D015394:Molecular Structure; D009163:Mycobacterium bovis / Q000187:drug effects*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity