Abstract
Trypanosoma cruzi is the causative agent of Chagas disease, a parasitic infection endemic in Latin America. In T. cruzi the transport of polyamines is essential because this organism is unable to synthesize these compounds de novo. Therefore, the uptake of polyamines from the extracellular medium is critical for survival of the parasite. The anthracene-putrescine conjugate Ant4 was first designed as a polyamine transport probe in cancer cells. Ant4 was also found to inhibit the polyamine transport system and produced a strong trypanocidal effect in T. cruzi. Considering that Ant4 is not currently approved by the FDA, in this work we performed computer simulations to find trypanocidal drugs approved for use in humans that have structures and activities similar to Ant4. Through a similarity ligand-based virtual screening using Ant4 as reference molecule, four possible inhibitors of polyamine transport were found. Three of them, promazine, chlorpromazine, and clomipramine, showed to be effective inhibitors of putrescine uptake, and also revealed a high trypanocidal activity against T. cruzi amastigotes (IC50 values of 3.8, 1.9, and 2.9 μM, respectively) and trypomastigotes (IC50 values of 3.4, 2.7, and 1.3 μM, respectively) while in epimastigotes the IC50 were significantly higher (34.7, 41.4, and 39.7 μM, respectively). Finally, molecular docking simulations suggest that the interactions between the T. cruzi polyamine transporter TcPAT12 and all the identified inhibitors occur in the same region of the protein. However, this location is different from the site occupied by the natural substrates. The value of this effort is that repurposing known drugs in the treatment of other pathologies, especially neglected diseases such as Chagas disease, significantly decreases the time and economic cost of implementation.
Highlights
The protozoan Trypanosoma cruzi is the causative agent of Chagas disease, a severe parasitic infection endemic in Latin America with ∼7 million infected and more than 70 million people at risk, mostly living in conditions of extreme poverty [1, 2]
Feature-based structure alignments were performed and the similarities were calculated as the number of matched feature pairs (MFP; i.e., aromatic ring, hydrophobic area, hydrogen bond donor or acceptor, negative or positive ionizable atom, and metal binding location)
At 25 μM the inhibitions observed were 64.6% (±2.7), 55.7% (±0.7), and 60.2% (±9.5) for PRM, CHL, and CLM, respectively. These results suggest that the compounds evaluated act through a polyamine transport inhibition mechanism in T. cruzi epimastigotes and trypomastigotes
Summary
The protozoan Trypanosoma cruzi is the causative agent of Chagas disease, a severe parasitic infection endemic in Latin America with ∼7 million infected and more than 70 million people at risk, mostly living in conditions of extreme poverty [1, 2]. The available drugs, benznidazole, and nifurtimox, have been used for nearly half a century and can cause severe side effects decreasing the quality of life of the patients. They are only partially effective in the treatment of the chronic phase of the disease, when most of the patients are diagnosed [3]. One of the most interesting chemical features of polyamines is the regularly spaced positive charges and their ability to form ionic interactions with other molecules [5] These low-molecular weight compounds are essential for cell survival because they are involved in a wide variety of metabolic processes. The most abundant polyamines in nature, putrescine, spermidine, and spermine participate in cell growth and proliferation, signal transduction, gene transcription, and translation processes [6]
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