Abstract
Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, affects between 6 and 7 million people worldwide, with an estimated 300,000 to 1 million of these cases in the United States. In the chronic phase of infection, T. cruzi can cause severe gastrointestinal and cardiac disease, which can be fatal. Currently, only benznidazole is clinically approved by the FDA for pediatric use to treat this infection in the USA. Toxicity associated with this compound has driven the search for new anti-Chagas agents. Drug repurposing is a particularly attractive strategy for neglected diseases, as pharmacological parameters and toxicity are already known for these compounds, reducing costs and saving time in the drug development pipeline. Here, we screened 7680 compounds from the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library, a collection of drugs or compounds with confirmed clinical safety, against T. cruzi. We identified seven compounds of interest with potent in vitro activity against the parasite with a therapeutic index of 10 or greater, including the previously unreported activity of the antiherpetic compound 348U87. These results provide the framework for further development of new T. cruzi leads that can potentially move quickly to the clinic.
Highlights
Trypanosoma cruzi, the causative agent of Chagas disease, is a protozoan parasite that is primarily transmitted to humans via triatomine insects during a blood meal
Current treatment options are very limited for Chagas disease; only benznidazole is clinically approved for pediatric use in the case of acute T. cruzi infections in the United States
C2C12 cells were seeded at a density of 100 cells per well, and CA-I/72 T. cruzi parasites were seeded at a density of 1500 cells per well, using a Multidrop Combi liquid handler (Thermo Scientific, Waltham, MA, USA)
Summary
Trypanosoma cruzi, the causative agent of Chagas disease, is a protozoan parasite that is primarily transmitted to humans via triatomine insects (known as kissing bugs) during a blood meal. One cost-effective strategy involves repurposing existing drugs with known toxicity and pharmacokinetic profiles for other indications [6] This has the potential to speed up drug development efforts, reduce costs, and lower the chance of adverse events presenting in clinical trials. We identified seven compounds with suitable selectivity indexes (SIs) for drug repurposing; two of these, the antiherpetic drug 348U87 and the serotonin receptor binder 3-[4[4-(2-Methoxyphenyl)piperazine-1-yl]butyl]-6-[2-[4-(4-fluorobenzoyl)piperidine-1-yl]ethyl]benzothiazole2(3H)-one, have not previously been reported as anti-Chagas compounds, and may target the parasite through a novel mechanism. These molecules form an attractive collection of lead molecules for potential drug repurposing to treat Chagas disease
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