Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase

Abstract

Liver pyruvate kinase (PKL) has recently emerged as a new target for non-alcoholic fatty liver disease (NAFLD), and inhibitors of this enzyme could represent a new therapeutic option. However, this breakthrough is complicated by selectivity issues since pyruvate kinase exists in four different isoforms. In this work, we report that ellagic acid (EA) and its derivatives, present in numerous fruits and vegetables, can inhibit PKL potently and selectively. Several polyphenolic analogues of EA were synthesized and tested to identify the chemical features responsible for the desired activity. Molecular modelling studies suggested that this inhibition is related to the stabilization of the PKL inactive state. This unique inhibition mechanism could potentially herald the development of new therapeutics for NAFLD.

Exploration of Novel Urolithin C Derivatives as Non-Competitive Inhibitors of Liver Pyruvate Kinase

“…Previously, we identified compound 1 as a non-competitive inhibitor with a sub-micromolar activity for PKL ( Table 1 ) but different selectivity for the PKR, PKM1, and PKM2 isoforms [ 14 ]. Considering that our previous effort to co-crystallize compound 1 with the enzyme failed, we decided to pursue a different approach.…”

“…The lactone moiety was removed to give a biaryl compound. Compound 1 was synthesized as previously described [ 14 ], while 2 (urolithin A) was commercially available. The other compounds were synthesized as described below.…”

“…Our group recently started an extensive program aimed at identifying new possible compounds to inhibit PKL [ 12 , 13 , 14 ]. These efforts resulted in the identification of two different classes of PKL inhibitors.…”

“…These efforts resulted in the identification of two different classes of PKL inhibitors. The first, based on anthraquinone derivatives, behaved as competitive inhibitors of ADP, while the second, based on ellagic acid, shows a non-competitive inhibition of the enzyme based on the interaction with an allosteric site [ 12 , 14 ]. Deconstruction and simplification of ellagic acid identified one of its metabolites, urolithin C ( 1 ), as a more soluble and bioavailable PKL inhibitor.…”

“…Our group recently started an extensive program aimed at identifying new possible compounds to inhibit PKL [12][13][14]. These efforts resulted in the identification of two Our group recently started an extensive program aimed at identifying new possible compounds to inhibit PKL [12][13][14]. These efforts resulted in the identification of two different classes of PKL inhibitors.…”