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Discovery of Leishmania Druggable Serine Proteases by Activity-Based Protein Profiling

Porta, Exequiel O.J.; Isern, Jaime A.; Kalesh, Karunakaran; Steel, Patrick G.

Discovery of Leishmania Druggable Serine Proteases by Activity-Based Protein Profiling Thumbnail


Authors

Jaime A. Isern

Karunakaran Kalesh



Abstract

Leishmaniasis are a group of diseases caused by parasitic protozoa of the genus Leishmania. Current treatments are limited by difficult administration, high cost, poor efficacy, toxicity, and growing resistance. New agents, with new mechanisms of action, are urgently needed to treat the disease. Although extensively studied in other organisms, serine proteases (SPs) have not been widely explored as antileishmanial drug targets. Herein, we report for the first time an activity-based protein profiling (ABPP) strategy to investigate new therapeutic targets within the SPs of the Leishmania parasites. Active-site directed fluorophosphonate probes (rhodamine and biotin-conjugated) were used for the detection and identification of active Leishmania serine hydrolases (SHs). Significant differences were observed in the SHs expression levels throughout the Leishmania life cycle and between different Leishmania species. Using iTRAQ-labelling-based quantitative proteomic mass spectrometry, we identified two targetable SPs in Leishmania mexicana: carboxypeptidase LmxM.18.0450 and prolyl oligopeptidase LmxM.36.6750. Druggability was ascertained by selective inhibition using the commercial serine protease inhibitors chymostatin, lactacystin and ZPP, which represent templates for future anti-leishmanial drug discovery programs. Collectively, the use of ABPP method complements existing genetic methods for target identification and validation in Leishmania.

Citation

Porta, E. O., Isern, J. A., Kalesh, K., & Steel, P. G. (2022). Discovery of Leishmania Druggable Serine Proteases by Activity-Based Protein Profiling. Frontiers in Pharmacology, 13, https://doi.org/10.3389/fphar.2022.929493

Journal Article Type Article
Acceptance Date Jun 21, 2022
Online Publication Date Jul 15, 2022
Publication Date 2022
Deposit Date Jul 20, 2022
Publicly Available Date Jul 20, 2022
Journal Frontiers in Pharmacology
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 13
DOI https://doi.org/10.3389/fphar.2022.929493

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distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the
original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with
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