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Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868

Parasitic roundworms (nematodes) cause destructive diseases, and immense suffering in humans and other animals around the world. The control of these parasites relies heavily on anthelmintic therapy, but treatment failures and resistance to these drugs are widespread. As efforts to develop vaccines...

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Autores principales: Taki, Aya C., Wang, Tao, Nguyen, Nghi N., Ang, Ching-Seng, Leeming, Michael G., Nie, Shuai, Byrne, Joseph J., Young, Neil D., Zheng, Yuanting, Ma, Guangxu, Korhonen, Pasi K., Koehler, Anson V., Williamson, Nicholas A., Hofmann, Andreas, Chang, Bill C. H., Häberli, Cécile, Keiser, Jennifer, Jabbar, Abdul, Sleebs, Brad E., Gasser, Robin B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9616048/
https://www.ncbi.nlm.nih.gov/pubmed/36313370
http://dx.doi.org/10.3389/fphar.2022.1014804
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author Taki, Aya C.
Wang, Tao
Nguyen, Nghi N.
Ang, Ching-Seng
Leeming, Michael G.
Nie, Shuai
Byrne, Joseph J.
Young, Neil D.
Zheng, Yuanting
Ma, Guangxu
Korhonen, Pasi K.
Koehler, Anson V.
Williamson, Nicholas A.
Hofmann, Andreas
Chang, Bill C. H.
Häberli, Cécile
Keiser, Jennifer
Jabbar, Abdul
Sleebs, Brad E.
Gasser, Robin B.
author_facet Taki, Aya C.
Wang, Tao
Nguyen, Nghi N.
Ang, Ching-Seng
Leeming, Michael G.
Nie, Shuai
Byrne, Joseph J.
Young, Neil D.
Zheng, Yuanting
Ma, Guangxu
Korhonen, Pasi K.
Koehler, Anson V.
Williamson, Nicholas A.
Hofmann, Andreas
Chang, Bill C. H.
Häberli, Cécile
Keiser, Jennifer
Jabbar, Abdul
Sleebs, Brad E.
Gasser, Robin B.
author_sort Taki, Aya C.
collection PubMed
description Parasitic roundworms (nematodes) cause destructive diseases, and immense suffering in humans and other animals around the world. The control of these parasites relies heavily on anthelmintic therapy, but treatment failures and resistance to these drugs are widespread. As efforts to develop vaccines against parasitic nematodes have been largely unsuccessful, there is an increased focus on discovering new anthelmintic entities to combat drug resistant worms. Here, we employed thermal proteome profiling (TPP) to explore hit pharmacology and to support optimisation of a hit compound (UMW-868), identified in a high-throughput whole-worm, phenotypic screen. Using advanced structural prediction and docking tools, we inferred an entirely novel, parasite-specific target (HCO_011565) of this anthelmintic small molecule in the highly pathogenic, blood-feeding barber’s pole worm, and in other socioeconomically important parasitic nematodes. The “hit-to-target” workflow constructed here provides a unique prospect of accelerating the simultaneous discovery of novel anthelmintics and associated parasite-specific targets.
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spelling pubmed-96160482022-10-29 Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868 Taki, Aya C. Wang, Tao Nguyen, Nghi N. Ang, Ching-Seng Leeming, Michael G. Nie, Shuai Byrne, Joseph J. Young, Neil D. Zheng, Yuanting Ma, Guangxu Korhonen, Pasi K. Koehler, Anson V. Williamson, Nicholas A. Hofmann, Andreas Chang, Bill C. H. Häberli, Cécile Keiser, Jennifer Jabbar, Abdul Sleebs, Brad E. Gasser, Robin B. Front Pharmacol Pharmacology Parasitic roundworms (nematodes) cause destructive diseases, and immense suffering in humans and other animals around the world. The control of these parasites relies heavily on anthelmintic therapy, but treatment failures and resistance to these drugs are widespread. As efforts to develop vaccines against parasitic nematodes have been largely unsuccessful, there is an increased focus on discovering new anthelmintic entities to combat drug resistant worms. Here, we employed thermal proteome profiling (TPP) to explore hit pharmacology and to support optimisation of a hit compound (UMW-868), identified in a high-throughput whole-worm, phenotypic screen. Using advanced structural prediction and docking tools, we inferred an entirely novel, parasite-specific target (HCO_011565) of this anthelmintic small molecule in the highly pathogenic, blood-feeding barber’s pole worm, and in other socioeconomically important parasitic nematodes. The “hit-to-target” workflow constructed here provides a unique prospect of accelerating the simultaneous discovery of novel anthelmintics and associated parasite-specific targets. Frontiers Media S.A. 2022-10-14 /pmc/articles/PMC9616048/ /pubmed/36313370 http://dx.doi.org/10.3389/fphar.2022.1014804 Text en Copyright © 2022 Taki, Wang, Nguyen, Ang, Leeming, Nie, Byrne, Young, Zheng, Ma, Korhonen, Koehler, Williamson, Hofmann, Chang, Häberli, Keiser, Jabbar, Sleebs and Gasser. 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 Pharmacology
Taki, Aya C.
Wang, Tao
Nguyen, Nghi N.
Ang, Ching-Seng
Leeming, Michael G.
Nie, Shuai
Byrne, Joseph J.
Young, Neil D.
Zheng, Yuanting
Ma, Guangxu
Korhonen, Pasi K.
Koehler, Anson V.
Williamson, Nicholas A.
Hofmann, Andreas
Chang, Bill C. H.
Häberli, Cécile
Keiser, Jennifer
Jabbar, Abdul
Sleebs, Brad E.
Gasser, Robin B.
Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868
title Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868
title_full Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868
title_fullStr Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868
title_full_unstemmed Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868
title_short Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868
title_sort thermal proteome profiling reveals haemonchus orphan protein hco_011565 as a target of the nematocidal small molecule umw-868
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9616048/
https://www.ncbi.nlm.nih.gov/pubmed/36313370
http://dx.doi.org/10.3389/fphar.2022.1014804
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