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.
2022-09-25 | PXD034868 | Pride
Kejun Yin