Dataset Information

ABX464 – structure-activity relationship in a model parasitic nematode and target deconvolution

ABSTRACT: Within the context of our anthelmintic discovery program, we recently identified and evaluated a quinoline derivative, called ABX464 or obefazimod, as a nematocidal candidate; synthesised a series of analogues which were assessed for activity against the free-living model nematode Caenorhabditis elegans; and predicted compound-target relationships by thermal proteome profiling (TPP) and in silico docking. Here, we logically extend(ed) this work and critically evaluate(d) the anthelmintic activity of ABX464 analogues on Haemonchus contortus (barber’s pole worm) – a highly pathogenic nematode of ruminant livestock. First, we tested a series of 44 analogues on H. contortus (larvae and adults) to investigate ABX464’s nematocidal pharmacophore, and identified one compound with greater potency than the parent compound, and also showed moderate activity against a select number of other parasitic nematodes (including Ancylostoma, Heligmosomoides and Strongyloides species). Using TPP and in silico modelling studies, we predicted protein HCON_00074590 (a predicted aldo-keto reductase) as a target candidate for ABX464 in H. contortus. Future work aims to optimise this compound as a nematocidal candidate and investigate its pharmacokinetic properties. Overall, this study presents the first steps towards the development of a new anthelmintic with a novel, distinct mechanism of action.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Haemonchus Contortus (barber Pole Worm)

TISSUE(S): Whole Body, Somatic Muscle Cell

DISEASE(S): Parasitic Helminthiasis Infectious Disease

SUBMITTER: Tao Wang

LAB HEAD: Robin Beat Gasser

PROVIDER: PXD046553 | Pride | 2024-02-07

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	221206_Tao_TW-5488_1-1.raw	Raw
	221206_Tao_TW-5488_1-2.raw	Raw
	221206_Tao_TW-5488_1-3.raw	Raw
	221206_Tao_TW-5488_1-4.raw	Raw
	221206_Tao_TW-5488_1-5.raw	Raw

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Publications

Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activity.

Shanley Harrison T HT Taki Aya C AC Nguyen Nghi N Wang Tao T Byrne Joseph J JJ Ang Ching-Seng CS Leeming Michael G MG Nie Shuai S Williamson Nicholas N Zheng Yuanting Y Young Neil D ND Korhonen Pasi K PK Hofmann Andreas A Chang Bill C H BCH Wells Tim N C TNC Häberli Cécile C Keiser Jennifer J Jabbar Abdul A Sleebs Brad E BE Gasser Robin B RB

International journal for parasitology. Drugs and drug resistance 20240123

Within the context of our anthelmintic discovery program, we recently identified and evaluated a quinoline derivative, called ABX464 or obefazimod, as a nematocidal candidate; synthesised a series of analogues which were assessed for activity against the free-living nematode Caenorhabditis elegans; and predicted compound-target relationships by thermal proteome profiling (TPP) and in silico docking. Here, we logically extended this work and critically evaluated the anthelmintic activity of ABX46 ...[more]

PMID: 38295619

Similar Datasets

Project 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.

Project description:Parasitic diseases of humans and other animals represent a major socioeconomic burden worldwide. In humans, parasitic worms (helminths) that cause neglected tropical diseases (NTDs) affect ~ billion people, equating to a burden of >12 million disability-adjusted life years (DALYs) (Hotez et al., 2014). In other animals, although challenging to quantitate, the disease impact of such helminths is major (Pedersen, et al., 2015; Charlier et al., 2020; Selzer and Epe, 2021), and some of these parasites are also transmissible to humans (i.e. zoonotic) (McCarthy et al., 2000; Gordon et al., 2016). The control of these diseases relies on diagnosis, treatment and management strategies, and anthelmintic treatment is usually a central component of a control campaign, as vaccines are not available for the vast majority of them. These treatments are not always highly efficacious/effective, and the reliance on them, particularly if they are used excessively in an uncontrolled (suppressive) manner, has led to the emergence and spread of anthelmintic resistances in parasitic worms (within 4-X generations; REF), particularly those of animals. Although the resistance status of worms of humans to available compounds is somewhat unclear (Prichard, 2005; Keiser and Utzinger, 2008; Vercruysse et al., 2011), this is not the case for worms of important production animals (e.g., sheep, goats and pigs), where such resistance(s) is/are widespread and essentially worldwide. In recent work, we established a high-throughput whole-organism, phenotypic assay for the screening of relatively large libraries of tens to hundreds of thousands of compounds, the subsequent evaluation of active compounds and structure-activity relationship (SAR) studies to strive toward the optimisation of the activity and potency of analogs, and the minimisation of side effects and toxicity (Taki et al., 2021b; Taki et al., 2021c; Shanley et al., 2022). However, our early discovery work has been hampered by not knowing the target(s) to which compounds might bind and how they might work. In recent years, there have been major advances in the development of methods for identifying drug-target interactions (reviewed by Mateus et al., 2021), which include affinity purification, activity-based protein profiling, kinobeads (for kinases), stability of proteins from rates of oxidation, protein painting, limited proteolysis/drug affinity responsive target stability and thermal proteome profiling (TPP). Published evidence (Savitski et al., 2014; Perrin et al., 2020; Selkrig et al., 2020) demonstrates clearly the exquisite capacity of TPP to define or infer target molecules in projects with a biomedical focus (e.g., cancer, autophagy or infectious disease), but this method has not yet been utilised to define an anthelmintic target. This context provides the very exciting prospect of being able to rapidly provide evidence of drug-target interactions. For these reasons, in the present study, we undertook a high-throughput whole-organism, phenotypic screen of a well-curated compound library, identified ‘hit’ compounds for evaluation, identified one candidate with lead-like characteristics and inferred the target of this promising small molecule in H. contortus.