High-throughput screening of the ReFRAME library identifies potential drug repurposing candidates forTrypanosoma cruzi

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 ~ 12,000 compounds from the ReFRAME library, a collection of drugs or compounds with confirmed clinical safety, against T. cruzi. We identified 7 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.

Challenges in Chagas Disease Drug Development

“…Probably the most prominent recent development in Chagas disease drug research has been the increased use of high-throughput phenotypic screening [ 93 , 94 , 95 ]. The requirement for large compound libraries, robotic sample handling equipment, expertise in parasite biology, and over-arching funding mechanisms has brought together both the academic and commercial sectors, with not-for-profit drug development agencies, such as the DND i .…”

Host-directed therapy, an untapped opportunity for antimalarial intervention

“…One example is the 12,000-compounds ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) library, an open-access drug repositioning screening set combining 3 widely used commercial drug databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects). This library has been screened against parasites such as Trypanosoma cruzi , 65 the malaria-related Crytposporidium, 66 and pathogenic amoebae, 67 as well as viruses such as Zika 68 and Lassa, 69 and it would be of great interest to implement a screen against malaria parasites.…”

Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

“…This cascade was further improved by the inclusion of three distinct in vitro assays: the slow replicating/cycling strain potency assay, the trypomastigote assay, and the extended duration washout assay [ 67 ]. Recently, Bernatchez et al (2020) screened 7680 compounds from the Repurposing, Focused Rescue, and Accelerated Medchem library, and identified seven lead compounds with potent in vitro activity against T. cruzi and good therapeutic index [ 68 ].…”