Allosteric FBPase inhibitors gain 10(5) times in potency when simultaneously binding two neighboring AMP sites.
Human fructose-1,6-bisphosphatase (FBPase, EC 3.1.3.11) is a key gluconeogenic enzyme, responsible for the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate, and thus presents an opportunity for the development of novel therapeutics focused on lowering the hepatic glucose production in type 2 diabetics. In its active form FBPase exists as a homotetramer and is allosterically regulated by AMP. In an HTS campaign aromatic sulfonylureas have been identified as FBPase inhibitors mimicking AMP. By bridging two adjacent allosteric binding sites using two aromatic sulfonylureas as anchor units and covalently linking them, it was possible to obtain dual binding AMP site inhibitors that exhibit a strong inhibitory effect.
Hebeisen
Paul
P
F. Hoffmann-La Roche Ltd, Discovery Research Basel, CH-4070 Basel, Switzerland. paul.hebeisen@roche.com
Kuhn
Bernd
B
Kohler
Philipp
P
Gubler
Marcel
M
Huber
Walter
W
Kitas
Eric
E
Schott
Brigitte
B
Benz
Jörg
J
Joseph
Catherine
C
Ruf
Armin
A
D000249:Adenosine Monophosphate / Q000737:chemistry*; D000284:Administration, Oral; D000495:Allosteric Site; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D013453:Sulfonylurea Compounds / Q000737:chemistry
D013453:Sulfonylurea Compounds; D000249:Adenosine Monophosphate; D006597:Fructose-Bisphosphatase; D005947:Glucose