Isoprenoid pathway as a valid target to control parasitic diseases

CHAO, MARÍA NOELIA; RODRIGUEZ, JUAN BAUTISTA; SZAJNMAN, SERGIO HERNÁN

Washington

Congreso; 254th ACS National Meeting; 2017

American Chemical Society

American trypanosomiasis is a chronic parasitosis caused by Trypanosoma cruzi, which is the largest parasitic disease burden of the Americas being one of the most important diseases in the world. 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 etiologic 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 target for many parasitic diseases. Certainly, isoprenoids are essential compounds of the cellular machinery of all organisms due to their roles in a variety of biological processes. For that reason, several enzymes of this pathway, particularly those involved in the synthesis of sterols and farnesyl diphosphate, have been reported to be excellent drug targets against pathogenic parasites caused by trypanosomatids and Apicomplexan parasites. In this sense, WC-9 (4-phenoxyphenoxyethyl thiocyanate) and 2-alkylaminoethyl-1,1-bisphosphonates, developed in our laboratory, proved to be effective inhibitors of the enzymatic activity of two key enzymes of 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 T. cruzi FPPS facilitated a rational approach 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, and as a continuation of our project aimed at searching for new 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.