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dc.contributor.authorPreston, S
dc.contributor.authorJiao, Y
dc.contributor.authorBaell, JB
dc.contributor.authorKeiser, J
dc.contributor.authorCrawford, S
dc.contributor.authorKoehler, AV
dc.contributor.authorWang, T
dc.contributor.authorSimpson, MM
dc.contributor.authorKaplan, RM
dc.contributor.authorCowley, KJ
dc.contributor.authorSimpson, KJ
dc.contributor.authorHofmann, A
dc.contributor.authorJabbar, A
dc.contributor.authorGasser, RB
dc.date.accessioned2020-12-21T01:32:36Z
dc.date.available2020-12-21T01:32:36Z
dc.date.issued2017-12-01
dc.identifierpii: S2211-3207(17)30039-8
dc.identifier.citationPreston, S., Jiao, Y., Baell, J. B., Keiser, J., Crawford, S., Koehler, A. V., Wang, T., Simpson, M. M., Kaplan, R. M., Cowley, K. J., Simpson, K. J., Hofmann, A., Jabbar, A. & Gasser, R. B. (2017). Screening of the 'Open Scaffolds' collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, 7 (3), pp.286-294. https://doi.org/10.1016/j.ijpddr.2017.05.004.
dc.identifier.issn2211-3207
dc.identifier.urihttp://hdl.handle.net/11343/256554
dc.description.abstractThe discovery and development of novel anthelmintic classes is essential to sustain the control of socioeconomically important parasitic worms of humans and animals. With the aim of offering novel, lead-like scaffolds for drug discovery, Compounds Australia released the 'Open Scaffolds' collection containing 33,999 compounds, with extensive information available on the physicochemical properties of these chemicals. In the present study, we screened 14,464 prioritised compounds from the 'Open Scaffolds' collection against the exsheathed third-stage larvae (xL3s) of Haemonchus contortus using recently developed whole-organism screening assays. We identified a hit compound, called SN00797439, which was shown to reproducibly reduce xL3 motility by ≥ 70%; this compound induced a characteristic, "coiled" xL3 phenotype (IC50 = 3.46-5.93 μM), inhibited motility of fourth-stage larvae (L4s; IC50 = 0.31-12.5 μM) and caused considerable cuticular damage to L4s in vitro. When tested on other parasitic nematodes in vitro, SN00797439 was shown to inhibit (IC50 = 3-50 μM) adults of Ancylostoma ceylanicum (hookworm) and first-stage larvae of Trichuris muris (whipworm) and eventually kill (>90%) these stages. Furthermore, this compound completely inhibited the motility of female and male adults of Brugia malayi (50-100 μM) as well as microfilariae of both B. malayi and Dirofilaria immitis (heartworm). Overall, these results show that SN00797439 acts against genetically (evolutionarily) distant parasitic nematodes i.e. H. contortus and A. ceylanicum [strongyloids] vs. B. malayi and D. immitis [filarioids] vs. T. muris [enoplid], and, thus, might offer a novel, lead-like scaffold for the development of a relatively broad-spectrum anthelmintic. Our future work will focus on assessing the activity of SN00797439 against other pathogens that cause neglected tropical diseases, optimising analogs with improved biological activities and characterising their targets.
dc.languageEnglish
dc.publisherELSEVIER SCI LTD
dc.titleScreening of the 'Open Scaffolds' collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes
dc.typeJournal Article
dc.identifier.doi10.1016/j.ijpddr.2017.05.004
melbourne.affiliation.departmentVeterinary Biosciences
melbourne.affiliation.departmentSchool of Ecosystem and Forest Sciences
melbourne.affiliation.departmentClinical Pathology
melbourne.affiliation.departmentUniversity General
melbourne.source.titleInternational Journal for Parasitology: Drugs and Drug Resistance
melbourne.source.volume7
melbourne.source.issue3
melbourne.source.pages286-294
dc.rights.licenseCC BY-NC-ND
melbourne.elementsid1223990
melbourne.contributor.authorKoehler, Anson
melbourne.contributor.authorCRAWFORD, SIMON
melbourne.contributor.authorSimpson, Kaylene
melbourne.contributor.authorJabbar, Abdul
melbourne.contributor.authorGasser, Robin
melbourne.contributor.authorWang, Tao
melbourne.contributor.authorJiao, Yaqing
melbourne.contributor.authorPreston, Sarah
melbourne.contributor.authorHOFMANN, ANDREAS
dc.identifier.eissn2211-3207
melbourne.accessrightsOpen Access


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