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Screening the Pathogen Box to Discover and Characterize New Cruzain and TbrCatL Inhibitors
Thales do Valle Moreira1, Luan Carvalho Martins1, Lucas Abreu Diniz1
1Molecular Modeling and Drug Design Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, 6627, Antônio Carlos Avenue, Belo Horizonte 31270-901, MG, Brazil.
Insights
New drug discovery efforts are underway for Chagas disease and Human African Trypanosomiasis. Researchers screened compounds against key targets, identifying promising inhibitors for these neglected tropical diseases.
Area of Science:
- Neglected tropical diseases
- Drug discovery
- Parasitology
Background:
- Chagas disease (caused by *Trypanosoma cruzi*) and Human African Trypanosomiasis (caused by *T. brucei*) affect millions globally.
- Current treatments for these parasitic diseases have limited efficacy and severe side effects, necessitating novel therapeutic agents.
Purpose of the Study:
- To screen the Pathogen Box collection for inhibitors of cruzain and *Tbr*CatL, validated drug targets for Chagas disease and Human African Trypanosomiasis, respectively.
- To identify and characterize novel chemical entities with potential antiparasitic activity.
Main Methods:
- Enzymatic assays were used to screen 400 compounds from the Pathogen Box collection.
- Hit validation, IC50 determination, and mechanism of inhibition studies were performed.
- Molecular docking was employed to predict the binding mode of a lead compound.
Main Results:
- Six compounds demonstrated inhibitory activity against cruzain and/or *Tbr*CatL, with IC50 values ranging from 0.46 ± 0.03 to 27 ± 3 µM.
- MMV687246 was identified as a mixed inhibitor of cruzain (K = 57 ± 6 µM).
- MMV688179 exhibited potent competitive inhibition of cruzain (K = 165 ± 63 nM), with its binding mode elucidated through docking.
Conclusions:
- The screening identified six promising hit compounds against validated targets for Chagas disease and Human African Trypanosomiasis.
- These compounds represent valuable starting points for medicinal chemistry optimization to develop new treatments for these neglected diseases.
Abstract:
Chagas disease and Human African Trypanosomiasis, caused by Trypanosoma cruzi and T. brucei, respectively, pose relevant health challenges throughout the world, placing 65 to 70 million people at risk each. Given the limited efficacy and severe side effects associated with current chemotherapy, new drugs are urgently needed for both diseases. Here, we report the screening of the Pathogen Box collection against cruzain and TbrCatL, validated targets for Chagas disease and Human African Trypanosomiasis, respectively. Enzymatic assays were applied to screen 400 compounds, validate hits, determine IC50 values and, when possible, mechanisms of inhibition. In this case, 12 initial hits were obtained and ten were prioritized for follow-up. IC50 values were obtained for six of them (hit rate = 1.5%) and ranged from 0.46 ± 0.03 to 27 ± 3 µM. MMV687246 was found to be a mixed inhibitor of cruzain (K = 57 ± 6 µM) while MMV688179 was found to be a competitive inhibitor of cruzain with a nanomolar potency (K = 165 ± 63 nM). A putative binding mode for MMV688179 was obtained by docking. The six hits discovered against cruzain and TbrCatL are of great interest for further optimization by the medicinal chemistry community.
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