Rational design of antiparasitic agents targeting the isoprenoid pathway

JUAN B. RODRIGUEZ; SERGIO H. SZAJNMAN

Simposio; Humboldt Kolleg - Expanding the Frontiers of Science: A Transdiciplinary Approach; 2022

Humbold Foundation

Trypanosoma cruzi is the etiologic agent of American trypanosomiasis. The number of infected people with T. cruzi diminished from 18 million (1991) to 6 million (2010), but it is still the most the prevalent parasitic disease in the Americas. On the other hand, Toxoplasma gondii is an opportunistic Apicomplexan parasite responsible for toxoplasmosis, which is able to infect humans and warm-blooded animals affecting close to one billion people worldwide. The current chemotherapy for Chagas disease and toxoplasmosis is unsatisfactory and there is a critical need to develop new safe drugs. For example, Chagas disease chemotherapy is still deficient and based on two empirically discovered drugs: nifurtimox (Lampit®, Bayer-El Salvador) and benznidazole (Abarax®, Elea-Argentina), which are not FDA-approved in the United States where they are available only from CDC under investigational protocols. However, benznidazole was recently FDA-approved drug but for paediatric use only. Our long-term goal is to find alternate drugs for the treatment of these parasitic diseases. Enzymes of isoprenoid pathway studied so far that are involved in the synthesis of sterols have been reported to be excellent drug targets against pathogenic parasites. For example, bisphosphonates have activity against T. cruzi growth targeting T. cruzi farnesyl diphosphate synthase (TcFPPS). T. gondii FPPS is a bifunctional enzyme that can catalyze the condensation of isopentenyl diphosphate with three allylic substrates forming not only 15-carbon FPP but also 20-carbon GGPP. T. cruzi squalene synthase (TcSQS) proved to be an interesting target for drug design. Aryloxyethyl selenocyanates are potent inhibitors of T. cruzi proliferation targeting TcSQS acting towards T. gondii as well. T. gondii does not synthesize cholesterol and imports it from the host suggesting that inhibitors of the host SQS could potentially affect T. gondii growth. Our hypothesis is that the isoprenoid pathway constitutes a major target for the treatment of parasitic diseases. To test this hypothesis, our specific aims are: to investigate the effect of bisphosphonates against TcFPPS and TgFPPS, and against T. cruzi and T. gondii cells, and perform SAR studies to assist drug design; to study the effect of aryloxyethyl selenocyanates against TcSQS, and also against T. cruzi and T. gondii cells.1–3[1]J. B. Rodriguez, C. Gallo-Rodriguez, ChemMedChem 2019, 14, 190–216.[2]J. B. Rodriguez, B. N. Falcone, S. H. Szajnman, Expert Opin. Drug Discov. 2016, 11, 307–320.[3]J. B. Rodríguez, B. N. Falcone and S. H. Szajnman. Expert Opin. Ther. Patents 2016, 26, 993–1015