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  1. Article ; Online: Aspartyl Protease Inhibitors as Anti-Filarial Drugs

    Liana Beld / Hyeim Jung / Christina A. Bulman / Bruce A. Rosa / Peter U. Fischer / James W. Janetka / Sara Lustigman / Judy A. Sakanari / Makedonka Mitreva

    Pathogens, Vol 11, Iss 707, p

    2022  Volume 707

    Abstract: The current treatments for lymphatic filariasis and onchocerciasis do not effectively kill the adult parasitic nematodes, allowing these chronic and debilitating diseases to persist in millions of people. Thus, the discovery of new drugs with ... ...

    Abstract The current treatments for lymphatic filariasis and onchocerciasis do not effectively kill the adult parasitic nematodes, allowing these chronic and debilitating diseases to persist in millions of people. Thus, the discovery of new drugs with macrofilaricidal potential to treat these filarial diseases is critical. To facilitate this need, we first investigated the effects of three aspartyl protease inhibitors (APIs) that are FDA-approved as HIV antiretroviral drugs on the adult filarial nematode, Brugia malayi and the endosymbiotic bacteria, Wolbachia . From the three hits, nelfinavir had the best potency with an IC 50 value of 7.78 µM, followed by ritonavir and lopinavir with IC 50 values of 14.3 µM and 16.9 µM, respectively. The three APIs have a direct effect on killing adult B. malayi after 6 days of exposure in vitro and did not affect the Wolbachia titers. Sequence conservation and stage-specific gene expression analysis identified Bm8660 as the most likely primary aspartic protease target for these drug(s). Immunolocalization using antibodies raised against the Bm8660 ortholog of Onchocerca volvulus showed it is strongly expressed in female B. malayi , especially in metabolically active tissues such as lateral and dorsal/ventral chords, hypodermis, and uterus tissue. Global transcriptional response analysis using adult female B. pahangi treated with APIs identified four additional aspartic proteases differentially regulated by the three effective drugs, as well as significant enrichment of various pathways including ubiquitin mediated proteolysis, protein kinases, and MAPK/AMPK/FoxO signaling. In vitro testing against the adult gastro-intestinal nematode Trichuris muris suggested broad-spectrum potential for these APIs. This study suggests that APIs may serve as new leads to be further explored for drug discovery to treat parasitic nematode infections.
    Keywords Neglected tropical diseases (NTDs) ; filarial nematodes ; macrofilaricidal ; anti-filarial drugs ; gastro-intestinal nematodes ; Trichuris ; Medicine ; R
    Subject code 572
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: A host receptor enables type 1 pilus-mediated pathogenesis of Escherichia coli pyelonephritis.

    Lisa K McLellan / Michael R McAllaster / Arthur S Kim / Ľubomíra Tóthová / Patrick D Olson / Jerome S Pinkner / Allyssa L Daugherty / Teri N Hreha / James W Janetka / Daved H Fremont / Scott J Hultgren / Herbert W Virgin / David A Hunstad

    PLoS Pathogens, Vol 17, Iss 1, p e

    2021  Volume 1009314

    Abstract: Type 1 pili have long been considered the major virulence factor enabling colonization of the urinary bladder by uropathogenic Escherichia coli (UPEC). The molecular pathogenesis of pyelonephritis is less well characterized, due to previous limitations ... ...

    Abstract Type 1 pili have long been considered the major virulence factor enabling colonization of the urinary bladder by uropathogenic Escherichia coli (UPEC). The molecular pathogenesis of pyelonephritis is less well characterized, due to previous limitations in preclinical modeling of kidney infection. Here, we demonstrate in a recently developed mouse model that beyond bladder infection, type 1 pili also are critical for establishment of ascending pyelonephritis. Bacterial mutants lacking the type 1 pilus adhesin (FimH) were unable to establish kidney infection in male C3H/HeN mice. We developed an in vitro model of FimH-dependent UPEC binding to renal collecting duct cells, and performed a CRISPR screen in these cells, identifying desmoglein-2 as a primary renal epithelial receptor for FimH. The mannosylated extracellular domain of human DSG2 bound directly to the lectin domain of FimH in vitro, and introduction of a mutation in the FimH mannose-binding pocket abolished binding to DSG2. In infected C3H/HeN mice, type 1-piliated UPEC and Dsg2 were co-localized within collecting ducts, and administration of mannoside FIM1033, a potent small-molecule inhibitor of FimH, significantly attenuated bacterial loads in pyelonephritis. Our results broaden the biological importance of FimH, specify the first renal FimH receptor, and indicate that FimH-targeted therapeutics will also have application in pyelonephritis.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease

    Rahul Tyagi / Christina A. Bulman / Fidelis Cho-Ngwa / Chelsea Fischer / Chris Marcellino / Michelle R. Arkin / James H. McKerrow / Case W. McNamara / Matthew Mahoney / Nancy Tricoche / Shabnam Jawahar / James W. Janetka / Sara Lustigman / Judy Sakanari / Makedonka Mitreva

    Pathogens, Vol 10, Iss 1, p

    2021  Volume 71

    Abstract: Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult ... ...

    Abstract Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult parasites (macrofilaricides) which survive and reproduce in the host for very long periods. To identify effective macrofilaricides, we carried out phenotypic screening of a library of 2121 approved drugs for clinical use against adult Brugia pahangi and prioritized the hits for further studies by integrating those results with a computational prioritization of drugs and associated targets. This resulted in the identification of 18 hits with anti-macrofilaricidal activity, of which two classes, azoles and aspartic protease inhibitors, were further expanded upon. Follow up screening against Onchocerca spp. (adult Onchocerca ochengi and pre-adult O. volvulus ) confirmed activity for 13 drugs (the majority having IC 50 < 10 μM), and a counter screen of a subset against L. loa microfilariae showed the potential to identify selective drugs that prevent adverse events when co-infected individuals are treated. Stage specific activity was also observed. Many of these drugs are amenable to structural optimization, and also have known canonical targets, making them promising candidates for further optimization that can lead to identifying and characterizing novel anti-macrofilarial drugs.
    Keywords parasitic nematodes ; filarial nematodes ; whole worm assay ; in vitro ; target class repurposing ; anthelmintics ; Medicine ; R
    Subject code 616
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Hepatocyte growth factor activator inhibitor-2 stabilizes Epcam and maintains epithelial organization in the mouse intestine

    Makiko Kawaguchi / Koji Yamamoto / Naoki Takeda / Tsuyoshi Fukushima / Fumiki Yamashita / Katsuaki Sato / Kenichiro Kitamura / Yoshitaka Hippo / James W. Janetka / Hiroaki Kataoka

    Communications Biology, Vol 2, Iss 1, Pp 1-

    2019  Volume 14

    Abstract: Makiko Kawaguchi et al. developed an inducible Spint2 knockout mouse model which exhibited extensive damage to the intestinal epithelium and resulted in death six days after tamoxifen-induced gene ablation. The extreme phenotype observed in this ... ...

    Abstract Makiko Kawaguchi et al. developed an inducible Spint2 knockout mouse model which exhibited extensive damage to the intestinal epithelium and resulted in death six days after tamoxifen-induced gene ablation. The extreme phenotype observed in this inducible line suggests an important role for Spint2 in maintenance of healthy intestinal epithelium.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Identification of small molecule enzyme inhibitors as broad-spectrum anthelmintics

    Rahul Tyagi / Mostafa A. Elfawal / Scott A. Wildman / Jon Helander / Christina A. Bulman / Judy Sakanari / Bruce A. Rosa / Paul J. Brindley / James W. Janetka / Raffi V. Aroian / Makedonka Mitreva

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 13

    Abstract: Abstract Targeting chokepoint enzymes in metabolic pathways has led to new drugs for cancers, autoimmune disorders and infectious diseases. This is also a cornerstone approach for discovery and development of anthelmintics against nematode and flatworm ... ...

    Abstract Abstract Targeting chokepoint enzymes in metabolic pathways has led to new drugs for cancers, autoimmune disorders and infectious diseases. This is also a cornerstone approach for discovery and development of anthelmintics against nematode and flatworm parasites. Here, we performed omics-driven knowledge-based identification of chokepoint enzymes as anthelmintic targets. We prioritized 10 of 186 phylogenetically conserved chokepoint enzymes and undertook a target class repurposing approach to test and identify new small molecules with broad spectrum anthelmintic activity. First, we identified and tested 94 commercially available compounds using an in vitro phenotypic assay, and discovered 11 hits that inhibited nematode motility. Based on these findings, we performed chemogenomic screening and tested 32 additional compounds, identifying 6 more active hits. Overall, 6 intestinal (single-species), 5 potential pan-intestinal (whipworm and hookworm) and 6 pan-Phylum Nematoda (intestinal and filarial species) small molecule inhibitors were identified, including multiple azoles, Tadalafil and Torin-1. The active hit compounds targeted three different target classes in humans, which are involved in various pathways, including carbohydrate, amino acid and nucleotide metabolism. Last, using representative inhibitors from each target class, we demonstrated in vivo efficacy characterized by negative effects on parasite fecundity in hamsters infected with hookworms.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article: Characterization of parasite-specific indels and their proposed relevance for selective anthelminthic drug targeting

    Wang, Qi / Bruce A. Rosa / Esley Heizer / James W. Janetka / Makedonka Mitreva / Scott A. Wildman

    Infection, genetics, and evolution. 2016 Apr., v. 39

    2016  

    Abstract: Insertions and deletions (indels) are important sequence variants that are considered as phylogenetic markers that reflect evolutionary adaptations in different species. In an effort to systematically study indels specific to the phylum Nematoda and ... ...

    Abstract Insertions and deletions (indels) are important sequence variants that are considered as phylogenetic markers that reflect evolutionary adaptations in different species. In an effort to systematically study indels specific to the phylum Nematoda and their structural impact on the proteins bearing them, we examined over 340,000 polypeptides from 21 nematode species spanning the phylum, compared them to non-nematodes and identified indels unique to nematode proteins in more than 3000 protein families. Examination of the amino acid composition revealed uneven usage of amino acids for insertions and deletions. The amino acid composition and cost, along with the secondary structure constitution of the indels, were analyzed in the context of their biological pathway associations. Species-specific indels could enable indel-based targeting for drug design in pathogens/parasites. Therefore, we screened the spatial locations of the indels in the parasite's protein 3D structures, determined the location of the indel and identified potential unique drug targeting sites. These indels could be confirmed by RNA-Seq data. Examples are presented illustrating the close proximity of some indels to established small-molecule binding pockets that can potentially facilitate selective targeting to the parasites and bypassing their host, thus reducing or eliminating the toxicity of the potential drugs. This study presents an approach for understanding the adaptation of pathogens/parasites at a molecular level, and outlines a strategy to identify such nematode-selective targets that remain essential to the organism. With further experimental characterization and validation, it opens a possible channel for the development of novel treatments with high target specificity, addressing both host toxicity and resistance concerns.
    Keywords amino acid composition ; amino acids ; drugs ; Nematoda ; parasites ; pathogens ; phylogeny ; polypeptides ; proteins ; sequence analysis ; toxicity
    Language English
    Dates of publication 2016-04
    Size p. 201-211.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 2037068-4
    ISSN 1567-1348
    ISSN 1567-1348
    DOI 10.1016/j.meegid.2016.01.025
    Database NAL-Catalogue (AGRICOLA)

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