Allosteric FBPase inhibitors gain 10(5) times in potency when simultaneously binding two neighboring AMP sites.

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Hebeisen P, Kuhn B, Kohler P, Gubler M, Huber W, Kitas E, Schott B, Benz J, Joseph C, Ruf A

Allosteric FBPase inhibitors gain 10(5) times in potency when simultaneously binding two neighboring AMP sites.

Bioorg Med Chem Lett. 2008 Aug 15;18(16):4708-12. doi: 10.1016/j.bmcl.2008.06.103. Epub 2008 Jul 5.

PubMed ID

18650089 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Adenosine phosphate	Fructose-1,6-bisphosphatase 1	Protein	Humans	Unknown	Antagonist	Details

Polypeptides

Name	UniProt ID
Fructose-1,6-bisphosphatase 1	P09467	Details