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Small Molecule Enhancers of Rapamycin-Induced TOR Inhibition Promote Autophagy, Reduce Toxicity in Huntington’s Disease Models and Enhance Killing of Mycobacteria by Macrophages

R. Andres Floto, Sovan Sarkar, Ethan O. Perlstein, Beate Kampmann, Stuart L. Schreiber and David C. Rubinsztein

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Upregulation of autophagy may have therapeutic benefit in a range of diseases that include 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 cell disease 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.

Addendum to:
Small Molecules Enhance Autophagy and Reduce Toxicity in Huntington's Disease Models
S. Sarkar, E.O. Perlstein, S. Imarisio, S. Pineau, A. Cordenier, R.L. Maglathlin, J.A. Webster, T.A. Lewis, C.J. O'Kane, S.L. Schreiber and D.C. Rubinsztein
Nat Chem Biol 2007; 3:331-8

Authors

R. Andres Floto

Cambridge Institute for Medical Research

Sovan Sarkar

Cambridge Institute for Medical Research

Ethan O. Perlstein

Broad Institute of Harvard and MIT

Beate Kampmann

Imperial College

Stuart L. Schreiber

Broad Institute of Harvard and MIT

David C. Rubinsztein

Department of Medical Genetics; Cambridge Institute for Medical Research; Cambridge UK

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.