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

Authors :
Aya C. Taki
Tao Wang
Nghi N. Nguyen
Ching-Seng Ang
Michael G. Leeming
Shuai Nie
Joseph J. Byrne
Neil D. Young
Yuanting Zheng
Guangxu Ma
Pasi K. Korhonen
Anson V. Koehler
Nicholas A. Williamson
Andreas Hofmann
Bill C. H. Chang
Cécile Häberli
Jennifer Keiser
Abdul Jabbar
Brad E. Sleebs
Robin B. Gasser
Source :
Frontiers in Pharmacology, Vol 13 (2022)
Publication Year :
2022
Publisher :
Frontiers Media S.A., 2022.

Abstract

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.

Details

Language :
English
ISSN :
16639812
Volume :
13
Database :
Directory of Open Access Journals
Journal :
Frontiers in Pharmacology
Publication Type :
Academic Journal
Accession number :
edsdoj.9c2e2b7509564909be768e1c02e98074
Document Type :
article
Full Text :
https://doi.org/10.3389/fphar.2022.1014804