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Editorial Board Chairs: Antonello Mai, Rainer Metternich. Assoc. Editors: David Peralta, Scott Williams (Sr)
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Online ISSN: 1860-7187
March 17, 2011
VIP: Hybrid Lipoic Acid Derivatives to Attack Prion Disease on Multiple Fronts
Salvatore Bongarzone, Hoang Ngoc Ai Tran, Andrea Cavalli, Marinella Roberti, Michela Rosini, Paolo Carloni, Giuseppe Legname, and Maria Laura Bolognesi*
Prion diseases, such as bovine spongiform encephalopathy (BSE) in cattle and variant Creutzfeldt–Jakob disease (CJD) in humans, are infectious neurodegenerative disorders in which the central nervous system is attacked by prions: abnormal insoluble amyloidogenic proteins. This event results in the steady deterioration of neurological functions and ultimately leads to death. At present, there is no approved treatment for prion diseases, and no drug candidates are expected to enter clinical trials soon.
It is extremely challenging to develop therapies for prion diseases and other major neurodegenerative diseases. The dominant drug discovery paradigm is one disease, one target, one molecule, which ignores the polyetiological nature of prion diseases and similar maladies. Thus, some researchers have suggested this paradigm as one possible factor in the ongoing failure of current neurotherapeutic drugs.
An alternative approach involves compound(s) that interact simultaneously with multiple targets. This polypharmacological approach is more promising because it is better at addressing the multifactorial and progressive pathophysiological processes involved in prion diseases.
In their Communication, Maria Laura Bolognesi (University of Bologna, Italy) and colleagues Giuseppe Legname and Paolo Carloni (SISSA, Trieste (Italy), and the German Research School for Simulation Sciences in Aachen) argue in support of the multitarget drug discovery strategy as a way to develop effective anti-prion agents. Their collaborative research effort has resulted in the discovery of the first rationally designed molecules endowed with different biological activities relevant for combating prion neurodegeneration. By linking the antioxidant fragment of natural lipoic acid together with heteroaromatic prion-recognition motifs, a new series of chimeric molecules were generated. These compounds display a multitarget profile, effectively countering both prion fibril formation and oxidative stress in a cell culture model of prion replication. The reported in vitro results make these compounds effective candidates for further in vivo investigations into their multiple biological properties against prion diseases.
Received February 7, 2011; published online March 15, 2011, DOI: 10.1002/cmdc.201100072.