Invited lecture: Squalene synthase and farnesyl diphosphate synthase as a target for antiparasitic agents

RODRIGUEZ, JUAN BAUTISTA

Porto

Conferencia; III Simposio Iberoamericano de Química Orgánica (III-SIBEAQO); 2016

SIBEAQO Committee

Chagas disease, a chronic parasitosis caused by Trypanosoma cruzi, is the largest parasitic disease burden of the Americas and can be considered as one of the most important diseases in the world. The only drugs to treat T. cruzi infection are nifurtimox (now discontinued) and benznidazole. Neither of these two compounds are FDA-approved drugs, and in the United States they are available only from CDC under investigational protocols.1 On the other hand, Toxoplasma gondii is an opportunistic protozoan parasite that is responsible for toxoplasmosis. T. gondii is able to infect humans and warm-blooded animals. Toxoplasmosis can be considered as one of the most prevalent parasitic diseases affecting close to one billion people worldwide. The current chemotherapy for toxoplasmosis is also still deficient. Isoprenoids are essential compounds of the cellular machinery of all organisms due to their roles in a variety of biological processes. Several enzymes of this pathway in trypanosomatids and Apicomplexan parasites, involved in the synthesis of sterols and farnesyl diphosphate, have been reported to be excellent drug targets against pathogenic parasites.2Prospects in antiparasitic drug research have changed substantially since the availability of the crystal structure of several complexes of 2-alkylaminoethyl-1,1-bisphosphonates with T. cruzi farnesyl diphosphate synthase (TcFPPS).3 These data at hand facilitate a rational approach to obtain new bisphosphonate inhibitors. FPPS of T. gondii is a bifunctional enzyme that catalyzes the condensation of isopentenyl diphosphate with three allylic substrates: dimethylallyl diphosphate, geranyl diphosphate, and farnesyl disphosphate. Recent antiparasitic agents targeting FPPS will be presented. On the other hand, and as a continuation of our project aimed at searching for new squalene synthase (SQS) inhibitors structurally related to the well-known antiparasitic agent WC-9, several structurally related analogues have been envisioned. Lately, it has been possible to obtain crystals of WC-9 bound to human SQS but all the attempts to do so with TcSQS are still unsuccessful. Therefore, the recent progresses made in our laboratory on new bisphosphonate derivatives targeting FPPS as well as WC-9 analogues targeting SQS will be presented.