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Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction

Human pathogenic trypanosomatid parasites harbor a unique form of peroxisomes termed glycosomes that are essential for parasite viability. We and others previously identified and characterized the essential Trypanosoma brucei ortholog TbPEX3, which is the membrane-docking factor for the cytosolic re...

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Autores principales: Li, Mengqiao, Gaussmann, Stefan, Tippler, Bettina, Ott, Julia, Popowicz, Grzegorz M, Schliebs, Wolfgang, Sattler, Michael, Erdmann, Ralf, Kalel, Vishal C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721105/
https://www.ncbi.nlm.nih.gov/pubmed/34988071
http://dx.doi.org/10.3389/fcell.2021.737159
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author Li, Mengqiao
Gaussmann, Stefan
Tippler, Bettina
Ott, Julia
Popowicz, Grzegorz M
Schliebs, Wolfgang
Sattler, Michael
Erdmann, Ralf
Kalel, Vishal C
author_facet Li, Mengqiao
Gaussmann, Stefan
Tippler, Bettina
Ott, Julia
Popowicz, Grzegorz M
Schliebs, Wolfgang
Sattler, Michael
Erdmann, Ralf
Kalel, Vishal C
author_sort Li, Mengqiao
collection PubMed
description Human pathogenic trypanosomatid parasites harbor a unique form of peroxisomes termed glycosomes that are essential for parasite viability. We and others previously identified and characterized the essential Trypanosoma brucei ortholog TbPEX3, which is the membrane-docking factor for the cytosolic receptor PEX19 bound to the glycosomal membrane proteins. Knockdown of TbPEX3 expression leads to mislocalization of glycosomal membrane and matrix proteins, and subsequent cell death. As an early step in glycosome biogenesis, the PEX3–PEX19 interaction is an attractive drug target. We established a high-throughput assay for TbPEX3–TbPEX19 interaction and screened a compound library for small-molecule inhibitors. Hits from the screen were further validated using an in vitro ELISA assay. We identified three compounds, which exhibit significant trypanocidal activity but show no apparent toxicity to human cells. Furthermore, we show that these compounds lead to mislocalization of glycosomal proteins, which is toxic to the trypanosomes. Moreover, NMR-based experiments indicate that the inhibitors bind to PEX3. The inhibitors interfering with glycosomal biogenesis by targeting the TbPEX3–TbPEX19 interaction serve as starting points for further optimization and anti-trypanosomal drug development.
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spelling pubmed-87211052022-01-04 Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction Li, Mengqiao Gaussmann, Stefan Tippler, Bettina Ott, Julia Popowicz, Grzegorz M Schliebs, Wolfgang Sattler, Michael Erdmann, Ralf Kalel, Vishal C Front Cell Dev Biol Cell and Developmental Biology Human pathogenic trypanosomatid parasites harbor a unique form of peroxisomes termed glycosomes that are essential for parasite viability. We and others previously identified and characterized the essential Trypanosoma brucei ortholog TbPEX3, which is the membrane-docking factor for the cytosolic receptor PEX19 bound to the glycosomal membrane proteins. Knockdown of TbPEX3 expression leads to mislocalization of glycosomal membrane and matrix proteins, and subsequent cell death. As an early step in glycosome biogenesis, the PEX3–PEX19 interaction is an attractive drug target. We established a high-throughput assay for TbPEX3–TbPEX19 interaction and screened a compound library for small-molecule inhibitors. Hits from the screen were further validated using an in vitro ELISA assay. We identified three compounds, which exhibit significant trypanocidal activity but show no apparent toxicity to human cells. Furthermore, we show that these compounds lead to mislocalization of glycosomal proteins, which is toxic to the trypanosomes. Moreover, NMR-based experiments indicate that the inhibitors bind to PEX3. The inhibitors interfering with glycosomal biogenesis by targeting the TbPEX3–TbPEX19 interaction serve as starting points for further optimization and anti-trypanosomal drug development. Frontiers Media S.A. 2021-12-20 /pmc/articles/PMC8721105/ /pubmed/34988071 http://dx.doi.org/10.3389/fcell.2021.737159 Text en Copyright © 2021 Li, Gaussmann, Tippler, Ott, Popowicz, Schliebs, Sattler, Erdmann and Kalel. https://creativecommons.org/licenses/by/4.0/This is an open-access article 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 these terms.
spellingShingle Cell and Developmental Biology
Li, Mengqiao
Gaussmann, Stefan
Tippler, Bettina
Ott, Julia
Popowicz, Grzegorz M
Schliebs, Wolfgang
Sattler, Michael
Erdmann, Ralf
Kalel, Vishal C
Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction
title Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction
title_full Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction
title_fullStr Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction
title_full_unstemmed Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction
title_short Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction
title_sort novel trypanocidal inhibitors that block glycosome biogenesis by targeting pex3–pex19 interaction
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721105/
https://www.ncbi.nlm.nih.gov/pubmed/34988071
http://dx.doi.org/10.3389/fcell.2021.737159
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