PXD048945

PXD048945 is an original dataset announced via ProteomeXchange.

Title	Comparative exploration of the anthelmintic candidate KM08948 in Haemonchus contortus and Caenorhabditis elegans
Description	Infections and diseases caused by parasitic nematodes have a major adverse impact on the health and productivity of animals and humans worldwide. The control of these parasites often relies heavily on the treatment with commercially available chemical compounds (anthelmintics). However, the excessive or uncontrolled use of these compounds in livestock animals has led to major challenges linked to drug resistance in nematodes. Therefore, there is a need to develop new anthelmintics with novel mechanism(s) of action. Recently, we identified a small molecule, KM08948, with nematocidal activity against the free-living model organism Caenorhabditis elegans. Here, we evaluated KM08948’s potential as an anthelmintic in a structure-activity relationship (SAR) study in C. elegans and in the highly pathogenic, blood-feeding Haemonchus contortus (barber’s pole worm), and explored the compound-target relationship using thermal proteome profiling (TPP). First, we synthesised and tested a series of 25 KM08948 analogues for nematocidal activity in both H. contortus (larvae and adults) and C. elegans (young adults), establishing a preliminary nematocidal pharmacophore for both species. We identified several compounds with marked activity against either H. contortus or C. elegans which had greater efficacy than KM08948, and found a significant divergence in compound bioactivity between these two nematode species. We also identified a KM08948 analogue, 25, that moderately inhibited the motility of adult female H. contortus in vitro. Subsequently, we inferred three H. contortus proteins (HCON_00134350, HCON_00021470 and HCON_00099760) and five C. elegans proteins (F30A10.9, F15B9.8, B0361.6, DNC-4 and UNC-11) that interacted directly with KM08948; however, no conserved protein target was shared between the two nematode species. Future work aims to extend the SAR investigation in these and other parasitic nematode species, and validate individual proteins identified here as targets of KM08948. Overall, the present study describes an evaluation of this anthelmintic candidate and highlights some challenges associated with early anthelmintic discovery.
HostingRepository	PRIDE
AnnounceDate	2024-04-22
AnnouncementXML	Submission_2024-04-21_20:40:29.002.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tao Wang
SpeciesList	scientific name: Haemonchus contortus (Barber pole worm); NCBI TaxID: 6289; scientific name: Caenorhabditis elegans; NCBI TaxID: 6239;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2024-01-28 18:47:01	ID requested
⏵ 1	2024-04-21 20:40:29	announced

10.1016/J.IJPDDR.2024.100534;

submitter keyword: Haemonchus contortus, Caenorhabditis elegans, LC-MS/MS

Robin Beat Gasser
contact affiliation	Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne
contact email	robinbg@unimelb.edu.au
lab head
Tao Wang
contact affiliation	The University of Melbourne
contact email	tao.wang1@unimelb.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD048945
     1. Label: PRIDE project
     2. Name: Comparative exploration of the anthelmintic candidate KM08948 in Haemonchus contortus and Caenorhabditis elegans