Structure And Inhibition Investigation Of Trans-prenyltransferases

Mevalonate pathway is an important metabolic pathway present in eukaryotes,and some bacteria and it plays a key role in many physiological processes by biosynthesizing terpenes,such as cholesterol,dolichol,and ubiquinone.So,many of key enzymes in this pathway can be viewed as drug targets.Farnesyl pyrophosphate synthase(FPPS)and dehydrosqualene synthase(CrtM)occupy the two branching points of this pathway.FPPS catalyzes the sequential condensation of dimethylallyl pyrophosphate(DMAPP)with isopentenyl pyrophosphate(IPP)to produce farnesyl pyrophosphate(FPP).FPPS inhibitors can improve the accumulation of its upstream product of DMAPP and IPP,which can be used as a phosphorus antigen to stimulate??T cells proliferation to enhance the killing effect on tumor cells.Carotenoid staphyloxanthin(STX)is essential for bacterial growth and/or invasiveness in vivo.The first step in its biosynthesis is condensation of two FPP molecules to form dehydrosqualene,catalyzed by the enzyme CrtM.CrtM inhibitors can enhance the killing effect of reactive oxygen species(ROS)toward Staphylococcus aureus.We developed 35 FPPS inhibitors bearing 3-pyrrolin-2-one scaffold,which was obtained through a convenient three-component reaction at room temperature.Currently we have enhanced the activity Ki values to 200 nM.These molecules also possess“drug-like” properties,making them viable leads for further medicinal chemistry optimization.For CrtM,we designed and synthesized 32 phosphonosulfonate(PS),5phosphonocarboxylate(PC)and 10 bisphosphonate(PP)inhibitors.4-22 is the most active CrtM inhibitor with Ki values of 6 nM,orders of magnitude more active than phosphonosulfonates.However,bisphosphonates were found of only modest activity in the context of STX inhibition,perhaps due to the poor cell uptake.Phosphonosulfonates are the most active STX inhibitors,among which 4-23 IC50 value is 1.2 ?M.In vivo,4-23 significantly protected mice from Staphylococcus aureus challenge and the survival rate can reach to 60% compared to the mock-treated.