Isoprenoid pathway as a valid target to control parasitic diseases

CHAO, MARÍA N.; SZAJNMAN S. H.; JUAN B. RODRIGUEZ

Ciudad Autónoma de Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedad Argentina de Protozoología

American trypanosomiasis is a chronic parasitosis caused by Trypanosoma cruzi, which is the largest parasitic disease burden of the Americas. The only drugs to treat T. cruzi infection are nifurtimox 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. In addition, the etiological agent for toxoplasmosis, Toxoplasma gondii is an opportunistic protozoan parasite that is able to infect humans and warm-blooded animals. This illness is one of the most prevalent parasitic diseases affecting close to one billion people worldwide. The current chemotherapy for toxoplasmosis is also still deficient. Isoprenoid biosynthesis has been selected as a target for many parasitic diseases caused by trypanosomatids and Apicomplexan parasites. In this sense, WC-9 and bisphosphonates, developed in our laboratory, proved to be effective inhibitors of the enzymic activity of two key enzymes of the isoprenoid biosynthesis, squalene synthase (SQS) and farnesyl diphosphate synthase (FPPS). The availability of the crystal structure of several complexes of 2-alkylaminoethyl-1,1-bisphosphonates with TcFPPS facilitated a rational design to obtain new bisphosphonate inhibitors. Besides, 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. On the other hand, aimed at searching new SQS inhibitors structurally related to WC-9, several optimized analogs have been envisioned. Therefore, the recent progresses made in our laboratory on new bisphosphonate derivatives targeting FPPS as well as WC-9 analogs targeting SQS will be presented.