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 ortholog TbPEX3, which is the membrane-docking factor for the cytosolic receptor PEX19 bound...
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Published in | Frontiers in cell and developmental biology Vol. 9; p. 737159 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
Frontiers Media S.A
20.12.2021
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Subjects | |
Online Access | Get full text |
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Summary: | 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
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
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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: Armando Jardim, McGill University, Canada This article was submitted to Membrane Traffic, a section of the journal Frontiers in Cell and Developmental Biology J. Fraser Glickman, The Rockefeller University, United States Paul Michels, University of Edinburgh, United Kingdom Edited by: Jorge E. Azevedo, Universidade do Porto, Portugal |
ISSN: | 2296-634X 2296-634X |
DOI: | 10.3389/fcell.2021.737159 |