Preclinical Studies in Anti-Trypanosomatidae Drug Development.

Area of Science:

• Neglected tropical diseases
• Parasitology
• Drug discovery

Background:

• Trypanosomatid parasites like *Leishmania*, *Trypanosoma cruzi*, and *Trypanosoma brucei* cause significant human diseases.
• Existing treatments for these diseases are limited and problematic.
• These infections disproportionately affect impoverished rural communities, perpetuating a cycle of disease and poverty.

Purpose of the Study:

• To identify novel anti-trypanosomatid agents with improved efficacy and safety profiles.
• To screen a diverse library of compounds for growth-inhibitory properties against key trypanosomatid parasites.
• To evaluate the toxicity of promising compounds against mammalian cells and in vivo models.

Main Methods:

• Screening of over 450 compounds from in-house and Pathogen Box libraries against *L. infantum, L. amazonensis, L. braziliensis, T. cruzi*, and *T. brucei*.
• Evaluation of compound toxicity towards murine macrophages.
• Assessment of lead compounds in in vivo murine models for cutaneous leishmaniasis and Chagas disease.

Main Results:

• 17 selective anti-*Leishmania* compounds were identified from the in-house library, with IC50 values ranging from 0.09 to 25 μM and selectivity index >10.
• Approximately 20% of Pathogen Box compounds showed anti-parasitic activity, including five novel compounds against *L. infantum*.
• Three of the novel Pathogen Box compounds demonstrated efficacy in a cutaneous leishmaniasis model, leading to 100% survival.
• An oral combination of three compounds controlled parasitemia in a Chagas disease model.
• Differential responses were observed between reference strains and field isolates of *Leishmania* to the tested compounds.

Conclusions:

• A novel drug candidate was identified with broad-spectrum activity against *Leishmania* and other Trypanosomatidae in vitro and in vivo.
• The identified candidate exhibits low toxicity to mammalian cells and low acute in vivo toxicity.
• These findings offer a promising avenue for developing new therapies against neglected trypanosomatid infections.