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Antiprotozoal Agents

Antiprotozoal Agents

Leishmaniasis is a widespread parasitic disease caused by several Leishmania species. It affects millions of people each year and remains a major public health problem in endemic regions. First-line treatment relies on pentavalent antimonials, including meglumine antimoniate and sodium stibogluconate. Even so, how these drugs work has not been fully clear, especially their interaction with parasite-specific biochemical pathways. One key target is trypanothione reductase (TR), an enzyme that...

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A Parasite Rescue and Transformation Assay for Antileishmanial Screening Against Intracellular Leishmania donovani Amastigotes in THP1 Human Acute Monocytic Leukemia Cell Line

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Profiling Serine Hydrolases in the Leishmania Host-Pathogen Interactome Using Cell-Permeable Activity-Based

Jaime A Isern¹, Exequiel O J Porta¹, Karunakaran Kalesh^2,3

¹Department of Chemistry, Durham University, Stockton Rd., Durham, DH1 3LE, UK.

Chembiochem : a European Journal of Chemical Biology

|March 27, 2025

Summary

Activity-based protein profiling identified 14 serine hydrolases in Leishmania mexicana, revealing significant changes in their activity across parasite life stages. Inhibiting these enzymes reduced parasite infectivity, highlighting their role as virulence factors.

Keywords:

Leishmania fluorophosphonate probes host–pathogen interactomes proteomics serine hydrolases

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Area of Science:

Parasitology
Biochemistry
Neglected Tropical Diseases

Background:

Leishmaniasis is a neglected tropical disease caused by Leishmania parasites, posing a significant global health challenge.
Treatment is complicated by parasite lifecycle stages and increasing drug resistance.
Understanding parasite-host interactions is crucial for developing new therapies.

Purpose of the Study:

To investigate serine hydrolases (SHs) in Leishmania mexicana using activity-based protein profiling (ABPP).
To analyze SH activity across different parasite lifecycle stages.
To explore the role of SHs as potential virulence factors and therapeutic targets.

Main Methods:

Employed cell-permeable fluorophosphonate probes for ABPP in Leishmania mexicana.
Utilized secondary reactions with affinity reagents for analysis.
Compared SH activity across promastigote and amastigote stages.
Tested the effect of a prolyl-oligopeptidase inhibitor on parasite infectivity.

Main Results:

Identified 14 SHs, including peptidases and lipases, in the L. mexicana proteome.
Observed significant changes in SH activity across parasite lifecycle stages.
Demonstrated that SHs are important virulence factors.
Found that Z-Pro-Prolinal reduced parasite infectivity by altering multiple SH targets.

Conclusions:

Intracellular ABPP provides insights into the Leishmania host-parasite interactome.
SHs are critical virulence factors in Leishmania mexicana.
Targeting SHs, such as with prolyl-oligopeptidase inhibitors, may offer a strategy to reduce parasite infectivity.