Veterinary Biosciences - Research Publications

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Author: Chang, Bill × Author: Hofmann, Andreas × Author: Korhonen, Pasi × Author: Young, Neil × End date: 2022 × Start date: 2020 × Type: Journal Article ×

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    Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868
    Taki, ACC ; Wang, T ; Nguyen, NNN ; Ang, C-S ; Leeming, MGG ; Nie, S ; Byrne, JJJ ; Young, NDD ; Zheng, Y ; Ma, G ; Korhonen, PKK ; Koehler, AVV ; Williamson, NAA ; Hofmann, A ; Chang, BCH ; Haeberli, C ; Keiser, J ; Jabbar, A ; Sleebs, BEE ; Gasser, RBB (FRONTIERS MEDIA SA, 2022-10-14)
    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.
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    Chromosome-scale Echinococcus granulosus (genotype G1) genome reveals the Eg95 gene family and conservation of the EG95-vaccine molecule
    Korhonen, PK ; Kinkar, L ; Young, ND ; Cai, H ; Lightowlers, MW ; Gauci, C ; Jabbar, A ; Chang, BCH ; Wang, T ; Hofmann, A ; Koehler, A ; Li, J ; Li, J ; Wang, D ; Yin, J ; Yang, H ; Jenkins, DJ ; Saarma, U ; Laurimae, T ; Rostami-Nejad, M ; Irshadullah, M ; Mirhendi, H ; Sharbatkhori, M ; Ponce-Gordo, F ; Simsek, S ; Casulli, A ; Zait, H ; Atoyan, H ; de la Rue, ML ; Romig, T ; Wassermann, M ; Aghayan, SA ; Gevorgyan, H ; Yang, B ; Gasser, RB (NATURE PORTFOLIO, 2022-03-03)
    Cystic echinococcosis is a socioeconomically important parasitic disease caused by the larval stage of the canid tapeworm Echinococcus granulosus, afflicting millions of humans and animals worldwide. The development of a vaccine (called EG95) has been the most notable translational advance in the fight against this disease in animals. However, almost nothing is known about the genomic organisation/location of the family of genes encoding EG95 and related molecules, the extent of their conservation or their functions. The lack of a complete reference genome for E. granulosus genotype G1 has been a major obstacle to addressing these areas. Here, we assembled a chromosomal-scale genome for this genotype by scaffolding to a high quality genome for the congener E. multilocularis, localised Eg95 gene family members in this genome, and evaluated the conservation of the EG95 vaccine molecule. These results have marked implications for future explorations of aspects such as developmentally-regulated gene transcription/expression (using replicate samples) for all E. granulosus stages; structural and functional roles of non-coding genome regions; molecular 'cross-talk' between oncosphere and the immune system; and defining the precise function(s) of EG95. Applied aspects should include developing improved tools for the diagnosis and chemotherapy of cystic echinococcosis of humans.