Signal peptide peptidase and gamma-secretase share equivalent inhibitor binding pharmacology.
The enzyme gamma-secretase has long been considered a potential pharmaceutical target for Alzheimer disease. Presenilin (the catalytic subunit of gamma-secretase) and signal peptide peptidase (SPP) are related transmembrane aspartyl proteases that cleave transmembrane substrates. SPP and gamma-secretase are pharmacologically similar in that they are targeted by many of the same small molecules, including transition state analogs, non-transition state inhibitors, and amyloid beta-peptide modulators. One difference between presenilin and SPP is that the proteolytic activity of presenilin functions only within a multisubunit complex, whereas SPP requires no additional protein cofactors for activity. In this study, gamma-secretase inhibitor radioligands were used to evaluate SPP and gamma-secretase inhibitor binding pharmacology. We found that the SPP enzyme exhibited distinct binding sites for transition state analogs, non-transition state inhibitors, and the nonsteroidal anti-inflammatory drug sulindac sulfide, analogous to those reported previously for gamma-secretase. In the course of this study, cultured cells were found to contain an abundance of SPP binding activity, most likely contributed by several of the SPP family proteins. The number of SPP binding sites was in excess of gamma-secretase binding sites, making it essential to use selective radioligands for evaluation of gamma-secretase binding under these conditions. This study provides further support for the idea that SPP is a useful model of inhibitory mechanisms and structure in the SPP/presenilin protein family.
Iben
Lawrence G
LG
Department of Neuroscience Drug Discovery and Applied Biotechnology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut 06492, USA.
Olson
Richard E
RE
Balanda
Lynn A
LA
Jayachandra
Sukhanya
S
Robertson
Barbara J
BJ
Hay
Vanessa
V
Corradi
John
J
Prasad
C V C
CV
Zaczek
Robert
R
Albright
Charles F
CF
Toyn
Jeremy H
JH
D000544:Alzheimer Disease / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D002460:Cell Line; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D053763:Presenilins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008024:Ligands; D053763:Presenilins; D011480:Protease Inhibitors; D013467:Sulindac; C025462:sulindac sulfide; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C460085:signal peptide peptidase