Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications.
Acid sphingomyelinase (ASM) is an important lipid-metabolizing enzyme cleaving sphingomyelin to ceramide, mainly within lysosomes. Acid ceramidase (AC) further degrades ceramide to sphingosine which can then be phosphorylated to sphingosine-1-phosphate. Ceramide and its metabolite sphingosine-1-phosphate have been shown to antagonistically regulate apoptosis, cellular differentiation, proliferation and cell migration. Inhibitors of ASM or AC therefore hold promise for a number of new clinical therapies, e.g. for Alzheimer's disease and major depression on the one hand and cancer on the other. Inhibitors of ASM have been known for a long time. Cationic amphiphilic substances induce the detachment of ASM protein from inner lysosomal membranes with its consecutive inactivation, thereby working as functional inhibitors of ASM. We recently experimentally identified a large number of hitherto unknown functional inhibitors of ASM and determined specific physicochemical properties of such cationic amphiphilic substances that functionally inhibit ASM. We propose the acronym "FIASMA" (Functional Inhibitor of Acid SphingoMyelinAse) for members of this large group of compounds with a broad range of new clinical indications. FIASMAs differ markedly with respect to molecular structure and current clinical indication. Most of the available FIASMAs are licensed for medical use in humans, are minimally toxic and may therefore be applied for disease states associated with increased activity of ASM.
Kornhuber
Johannes
J
Department of Psychiatry and Psychotherapy, University of Erlangen, Erlangen, Germany. Johannes.Kornhuber@uk-erlangen.de
Tripal
Philipp
P
Reichel
Martin
M
Mühle
Christiane
C
Rhein
Cosima
C
Muehlbacher
Markus
M
Groemer
Teja W
TW
Gulbins
Erich
E
D055573:Acid Ceramidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy; D002986:Clinical Trials as Topic; D003891:Desipramine / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D010726:Phosphodiesterase Inhibitors; D013108:Sphingomyelin Phosphodiesterase; D055573:Acid Ceramidase; D003891:Desipramine