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Lead identification to clinical candidate selection: drugs for Chagas disease
R Jeffrey Neitz1, Steven Chen1, Frantisek Supek2
1Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
Insights
Researchers identified new drug candidates for Chagas disease, a parasitic infection causing heart failure. A public-private partnership screened over 160,000 compounds to find novel anti-parasitic scaffolds.
Area of Science:
- Neglected tropical diseases
- Drug discovery and development
- Parasitology
Background:
- Chagas disease affects 8 million globally, causing significant heart failure deaths in Latin America.
- An estimated 300,000 cases exist in the United States, with no FDA-approved treatments.
- A public-private partnership was formed to address this critical unmet medical need.
Purpose of the Study:
- To discover novel clinical candidates for treating Chagas disease.
- To identify and develop new anti-Trypanosoma cruzi scaffolds.
- To compare different screening methodologies for antiparasitic drug discovery.
Main Methods:
- Screening of over 160,000 compounds from the GNF Academic Collaboration Library.
- Utilized and compared two screening methods: a colorimetric assay and high-content screening (HCS) assay.
- Evaluated structure-activity relationships for antiparasitic efficacy and pharmacokinetics.
Main Results:
- Identified new anti-Chagas scaffolds from the compound library.
- Ergosterol biosynthesis inhibitors showed differential potency between the two screening assays.
- A novel xanthine-derived scaffold targeting Trypanosoma cruzi was discovered and advanced as a lead series.
Conclusions:
- The study successfully identified promising new scaffolds for Chagas disease drug development.
- Comparative analysis of screening methods provided valuable insights for antiparasitic drug discovery.
- The identified xanthine-derived scaffold represents a significant advancement in the search for effective Chagas disease treatments.
Abstract:
Chagas disease affects 8 million people worldwide and remains a main cause of death due to heart failure in Latin America. The number of cases in the United States is now estimated to be 300,000, but there are currently no Food and Drug Administration (FDA)-approved drugs available for patients with Chagas disease. To fill this gap, we have established a public-private partnership between the University of California, San Francisco and the Genomics Institute of the Novartis Research Foundation (GNF) with the goal of delivering clinical candidates to treat Chagas disease. The discovery phase, based on the screening of more than 160,000 compounds from the GNF Academic Collaboration Library, led to the identification of new anti-Chagas scaffolds. Part of the screening campaign used and compared two screening methods, including a colorimetric-based assay using Trypanosoma cruzi expressing β-galactosidase and an image-based, high-content screening (HCS) assay using the CA-I/72 strain of T. cruzi. Comparing molecules tested in both assays, we found that ergosterol biosynthesis inhibitors had greater potency in the colorimetric assay than in the HCS assay. Both assays were used to inform structure-activity relationships for antiparasitic efficacy and pharmacokinetics. A new anti-T. cruzi scaffold derived from xanthine was identified, and we describe its development as lead series.
