Giardia lamblia G6PD::6PGL Fused Protein Inhibitors Decrease Trophozoite Viability: A New Alternative against...

Area of Science:

• Parasitology
• Medicinal Chemistry
• Biochemistry

Background:

• Current giardiasis treatments face challenges due to drug resistance and toxicity.
• Enzyme inhibition presents a novel strategy for targeting protozoan parasites.
• The bifunctional Glucose-6-phosphate dehydrogenase and 6-phosphogluconolactonase (G6PD::6PGL) enzyme in Giardia lamblia is a potential drug target.

Purpose of the Study:

• To identify potent inhibitors of the Giardia lamblia G6PD::6PGL enzyme.
• To evaluate the antigiardial activity and selectivity of identified compounds.
• To explore novel therapeutic strategies against giardiasis.

Main Methods:

• Inhibition assays were performed using an in-house chemical library and four target compounds (CNZ-7, CNZ-8, CMC-1, FLP-2).
• Enzyme kinetics and biophysical methods were used to characterize inhibitor interactions.
• Antiparasitic activity was assessed in Giardia lamblia trophozoites, and cytotoxicity was evaluated in human cell lines (Caco-2, HT29).

Main Results:

• Four compounds (CNZ-7, CNZ-8, CMC-1, FLP-2) demonstrated potent inhibition of the G. lamblia G6PD::6PGL enzyme.
• These inhibitors altered the enzyme's secondary and tertiary structure and global stability.
• The compounds exhibited significant antigiardial activity with IC50 values ranging from 8.7 to 24.1 µM and low toxicity in human cells.

Conclusions:

• The identified compounds are promising starting points for developing new antigiardial drugs.
• Targeting the G. lamblia G6PD::6PGL enzyme offers a selective approach to combat giardiasis.
• The low toxicity profile suggests potential for safer therapeutic agents.