Frontiers in Pharmacology (Oct 2022)
Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868
- 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,
- Guangxu Ma,
- Pasi K. Korhonen,
- Anson V. Koehler,
- Nicholas A. Williamson,
- Andreas Hofmann,
- Bill C. H. Chang,
- Cécile Häberli,
- Cécile Häberli,
- Jennifer Keiser,
- Jennifer Keiser,
- Abdul Jabbar,
- Brad E. Sleebs,
- Brad E. Sleebs,
- Brad E. Sleebs,
- Robin B. Gasser
Affiliations
- Aya C. Taki
- Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
- Tao Wang
- Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
- Nghi N. Nguyen
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Ching-Seng Ang
- Melbourne Mass Spectrometry and Proteomics Facility, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
- Michael G. Leeming
- Melbourne Mass Spectrometry and Proteomics Facility, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
- Shuai Nie
- Melbourne Mass Spectrometry and Proteomics Facility, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
- Joseph J. Byrne
- Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
- Neil D. Young
- Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
- Yuanting Zheng
- Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
- Guangxu Ma
- Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
- Guangxu Ma
- Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Institute of Preventive Veterinary Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Pasi K. Korhonen
- Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
- Anson V. Koehler
- Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
- Nicholas A. Williamson
- Melbourne Mass Spectrometry and Proteomics Facility, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
- Andreas Hofmann
- Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
- Bill C. H. Chang
- Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
- Cécile Häberli
- Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Allschwil, Switzerland
- Cécile Häberli
- University of Basel, Basel, Switzerland
- Jennifer Keiser
- Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Allschwil, Switzerland
- Jennifer Keiser
- University of Basel, Basel, Switzerland
- Abdul Jabbar
- Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
- Brad E. Sleebs
- Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
- Brad E. Sleebs
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Brad E. Sleebs
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
- Robin B. Gasser
- Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
- DOI
- https://doi.org/10.3389/fphar.2022.1014804
- Journal volume & issue
-
Vol. 13
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.
Keywords
- thermal proteome profiling
- anthelmintic discovery
- target identification
- structure modelling
- in silico docking
