Glyceraldehyde-3-phosphate dehydrogenase, the putative target of the antiapoptotic compounds CGP 3466 and R-(-)-deprenyl.
R-(-)-Deprenyl (Selegiline) represents one of the drugs currently used for the treatment of Parkinson's disease. This compound was shown to protect neurons or glias from programmed cell death in a variety of models. The mechanism of action of neuroprotection as well as inhibition of apoptosis remains elusive. CGP 3466 is a structurally related analog of R-(-)-deprenyl that exhibits virtually no monoamine oxidase type B inhibiting activity but is neuroprotective in the picomolar concentration range. We showed specific binding of CGP 3466 to glyceraldehyde-3-phosphate dehydrogenase by affinity binding, by affinity labeling, and by means of BIAcore(R) technology. Apoptosis assays based on the human neuroblastoma cell line PAJU established the importance of this interaction for mediating drug-induced inhibition of programmed cell death.
Kragten
E
E
Novartis Pharma Research, Core Technology Area, CH-4002 Basel, Switzerland.
Lalande
I
I
Zimmermann
K
K
Roggo
S
S
Schindler
P
P
Muller
D
D
van Oostrum
J
J
Waldmeier
P
P
Furst
P
P
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015374:Biosensing Techniques; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation / Q000235:genetics; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D009132:Muscles / Q000201:enzymology; D009447:Neuroblastoma / Q000378:metabolism; D018696:Neuroprotective Agents; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010082:Oxepins / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy; D019920:Photoaffinity Labels / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D011817:Rabbits; D051381:Rats; D012642:Selegiline / Q000031:analogs & derivatives / Q000494:pharmacology*
D000978:Antiparkinson Agents; D018696:Neuroprotective Agents; D016376:Oligonucleotides, Antisense; D010082:Oxepins; D019920:Photoaffinity Labels; D011437:Propylamines; C111178:dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine; D012642:Selegiline; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases