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Evaluation of the Leishmania inositol phosphorylceramide synthase as a drug target using a chemical and genetic approach (2024)
Journal Article
Alpizar-Sosa, E. A., Zimbres, F. M., Mantilla, B. S., Dickie, E. A., Wei, W., Burle-Caldas, G. A., Filipe, L. N., Van Bocxlaer, K., Price, H. P., Ibarra-Meneses, A. V., Beaudry, F., Fernandez-Prada, C., Whitfield, P. D., Barrett, M. P., & Denny, P. W. (2024). Evaluation of the Leishmania inositol phosphorylceramide synthase as a drug target using a chemical and genetic approach. ACS Infectious Diseases, https://doi.org/10.1021/acsinfecdis.4c00284

The lack of effective vaccines and the development of resistance to the current treatments highlight the urgent need for new anti-leishmanials. Sphingolipid metabolism has been proposed as a promising source of -specific targets as these lipids are... Read More about Evaluation of the Leishmania inositol phosphorylceramide synthase as a drug target using a chemical and genetic approach.

Rapid genotyping of Toxoplasma gondii isolates via Nanopore-based multi-locus sequencing (2024)
Journal Article
Koutsogiannis, Z., & Denny, P. W. (2024). Rapid genotyping of Toxoplasma gondii isolates via Nanopore-based multi-locus sequencing. AMB Express, 14(1), Article 68. https://doi.org/10.1186/s13568-024-01728-x

Toxoplasma gondii is an obligate intracellular parasite associated with severe disease, especially in the immunosuppressed. It is also a cause of congenital malformation and abortion in both animals and humans and is considered one of the most import... Read More about Rapid genotyping of Toxoplasma gondii isolates via Nanopore-based multi-locus sequencing.

TREATMENT OF LEISHMANIASIS (2024)
Patent
Denny, P., Steel, P., & Lyne, V. (2024). TREATMENT OF LEISHMANIASIS. WO 2024/084186 A1

The invention relates to compounds of formula (I), which may be used in the treatment of microbial infections. In particular, compounds of formula (I) are effective at treating leishmaniasis. The invention extends to novel compositions, therapies and... Read More about TREATMENT OF LEISHMANIASIS.

Clemastine/tamoxifen hybrids as easily accessible antileishmanial drug leads (2024)
Journal Article
Agostino, V. S., Buerdsell, M. L., Uliana, S. R. B., Denny, P. W., Coelho, A. C., & Steel, P. G. (2024). Clemastine/tamoxifen hybrids as easily accessible antileishmanial drug leads. Organic and Biomolecular Chemistry, 22(9), 1812-1820. https://doi.org/10.1039/d3ob02091f

A library of hybrid molecules is developed based on the common chemical features shared by clemastine and tamoxifen both of which are well known for their antileishmanial activities. In the initial screening against Leishmania major and L. amazonensi... Read More about Clemastine/tamoxifen hybrids as easily accessible antileishmanial drug leads.

Inhibition of HSP90 distinctively modulates the global phosphoproteome of Leishmania mexicana developmental stages (2023)
Journal Article
Porta, E. O., Gao, L., Denny, P. W., Steel, P. G., & Kalesh, K. (2023). Inhibition of HSP90 distinctively modulates the global phosphoproteome of Leishmania mexicana developmental stages. Microbiology Spectrum, 11(6), Article e02960-23. https://doi.org/10.1128/spectrum.02960-23

Heat shock protein 90 (HSP90) is an evolutionarily conserved chaperone protein that plays a central role in the folding and maturation of a large array of client proteins. In the unicellular parasite Leishmania, the etiological agent of the neglected... Read More about Inhibition of HSP90 distinctively modulates the global phosphoproteome of Leishmania mexicana developmental stages.

Toxoplasma ceramide synthases: Gene duplication, functional divergence, and roles in parasite fitness. (2023)
Journal Article
Koutsogiannis, Z., Mina, J. G., Albus, C. A., Kol, M. A., Holthuis, J. C. M., Pohl, E., & Denny, P. W. (2023). Toxoplasma ceramide synthases: Gene duplication, functional divergence, and roles in parasite fitness. FASEB Journal, 37(11), Article e23229. https://doi.org/10.1096/fj.202201603RRR

Toxoplasma gondii is an obligate, intracellular apicomplexan protozoan parasite of both humans and animals that can cause fetal damage and abortion and severe disease in the immunosuppressed. Sphingolipids have indispensable functions as signaling mo... Read More about Toxoplasma ceramide synthases: Gene duplication, functional divergence, and roles in parasite fitness..

Disruption of the inositol phosphorylceramide synthase gene affects Trypanosoma cruzi differentiation and infection capacity (2023)
Journal Article
Dos Santos, N. S. A., Estevez-Castro, C. F., Macedo, J. P., Chame, D. F., Castro-Gomes, T., Santos-Cardoso, M., …Teixeira, S. M. R. (2023). Disruption of the inositol phosphorylceramide synthase gene affects Trypanosoma cruzi differentiation and infection capacity. PLoS Neglected Tropical Diseases, 17(9), Article e0011646. https://doi.org/10.1371/journal.pntd.0011646

Sphingolipids (SLs) are essential components of all eukaryotic cellular membranes. In fungi, plants and many protozoa, the primary SL is inositol-phosphorylceramide (IPC). Trypanosoma cruzi is a protozoan parasite that causes Chagas disease (CD), a c... Read More about Disruption of the inositol phosphorylceramide synthase gene affects Trypanosoma cruzi differentiation and infection capacity.

Assessment of Toxoplasma gondii lytic cycle and the impact of a gene deletion using 3D label-free optical diffraction holotomography (2023)
Journal Article
Koutsogiannis, Z., Mina, J. G. M., Suman, R., & Denny, P. W. (2023). Assessment of Toxoplasma gondii lytic cycle and the impact of a gene deletion using 3D label-free optical diffraction holotomography. Frontiers in Cellular and Infection Microbiology, 13, Article 1237594. https://doi.org/10.3389/fcimb.2023.1237594

Toxoplasma gondii is a widespread single-celled intracellular eukaryotic apicomplexan protozoan parasite primarily associated with mammalian foetal impairment and miscarriage, including in humans. Is estimated that approximately one third of the huma... Read More about Assessment of Toxoplasma gondii lytic cycle and the impact of a gene deletion using 3D label-free optical diffraction holotomography.

Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response (2022)
Journal Article
Alpizer-Sosa, E., Ithnin, N., Wei, W., Pountain, A., Weidt, A., Donachie, A., …Barrett, M. (2022). Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response. PLoS Neglected Tropical Diseases, 16(9), Article e0010779. https://doi.org/10.1371/journal.pntd.0010779

Amphotericin B is increasingly used in treatment of leishmaniasis. Here, fourteen independent lines of Leishmania mexicana and one L. infantum line were selected for resistance to either amphotericin B or the related polyene antimicrobial, nystatin.... Read More about Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response.

Genome deletions to overcome the directed loss of gene function in Leishmania (2022)
Journal Article
Alpizar-Sosa, E., Kumordzi, Y., Wei, W., Whitfield, P., Barrett, M., & Denny, P. (2022). Genome deletions to overcome the directed loss of gene function in Leishmania. Frontiers in Cellular and Infection Microbiology, 12, https://doi.org/10.3389/fcimb.2022.988688

With the global reach of the Neglected Tropical Disease leishmanaisis increasing, coupled with a tiny armoury of therapeutics which all have problems with resistance, cost, toxicity and/or administration, the validation of new drug targets in the cau... Read More about Genome deletions to overcome the directed loss of gene function in Leishmania.

Illuminating Host-Parasite Interaction at the Cellular and Subcellular Levels with Infrared Microspectroscopy (2022)
Journal Article
Elsheikha, H. M., Al-Sandaqchi, A. T., Harun, M. S., Winterton, F., Altharawi, A., Elsaied, N. A., …Chan, K. L. A. (2022). Illuminating Host-Parasite Interaction at the Cellular and Subcellular Levels with Infrared Microspectroscopy. Cells, 11(5), Article 811. https://doi.org/10.3390/cells11050811

Toxoplasma gondii (T. gondii) is an opportunistic protozoan that can cause brain infection and other serious health consequences in immuno-compromised individuals. This parasite has a remarkable ability to cross biological barriers and exploit the ho... Read More about Illuminating Host-Parasite Interaction at the Cellular and Subcellular Levels with Infrared Microspectroscopy.

Transcriptome-Wide Identification of Coding and Noncoding RNA-Binding Proteins Defines the Comprehensive RNA Interactome of Leishmania mexicana (2022)
Journal Article
Kalesh, K., Wei, W., Mantilla, B., Roumeliotis, T., Choudhary, J., & Denny, P. (2022). Transcriptome-Wide Identification of Coding and Noncoding RNA-Binding Proteins Defines the Comprehensive RNA Interactome of Leishmania mexicana. Microbiology Spectrum, 10(1), e02422-21. https://doi.org/10.1128/spectrum.02422-21

Proteomic profiling of RNA-binding proteins in Leishmania is currently limited to polyadenylated mRNA-binding proteins, leaving proteins that interact with nonadenylated RNAs, including noncoding RNAs and pre-mRNAs, unidentified. Using a combination... Read More about Transcriptome-Wide Identification of Coding and Noncoding RNA-Binding Proteins Defines the Comprehensive RNA Interactome of Leishmania mexicana.

The Histidine Ammonia Lyase of Trypanosoma cruzi is Involved in Acidocalcisome Alkalinization and is Essential for Survival under Starvation Conditions (2021)
Journal Article
Mantilla, B., Azevedo, C., Denny, P., Saiardi, A., & Docampo, R. (2021). The Histidine Ammonia Lyase of Trypanosoma cruzi is Involved in Acidocalcisome Alkalinization and is Essential for Survival under Starvation Conditions. mBio, 12(6), https://doi.org/10.1128/mbio.01981-21

Trypanosoma cruzi, the agent of Chagas disease, accumulates polyphosphate (polyP) and Ca2+ inside acidocalcisomes. The alkalinization of this organelle stimulates polyP hydrolysis and Ca2+ release. Here, we report that histidine ammonia lyase (HAL),... Read More about The Histidine Ammonia Lyase of Trypanosoma cruzi is Involved in Acidocalcisome Alkalinization and is Essential for Survival under Starvation Conditions.

Chalcones identify cTXNPx as a potential antileishmanial drug target (2021)
Journal Article
Escrivani, D. O., Charlton, R. L., Caruso, M. B., Burle-Caldas, G. A., Borsodi, M. P. G., Zingali, R. B., …Steel, P. G. (2021). Chalcones identify cTXNPx as a potential antileishmanial drug target. PLoS Neglected Tropical Diseases, 15(11), Article e0009951. https://doi.org/10.1371/journal.pntd.0009951

With current drug treatments failing due to toxicity, low efficacy and resistance; leishmaniasis is a major global health challenge that desperately needs new validated drug targets. Inspired by activity of the natural chalcone 2’,6’-dihydroxy-4’-met... Read More about Chalcones identify cTXNPx as a potential antileishmanial drug target.

Quantitative Proteomics Reveals that Hsp90 Inhibition Dynamically Regulates Global Protein Synthesis in Leishmania mexicana (2021)
Journal Article
Karunakaran, K., Sundriyal, S., Perera, H., Cobb, S. L., & Denny, P. W. (online). Quantitative Proteomics Reveals that Hsp90 Inhibition Dynamically Regulates Global Protein Synthesis in Leishmania mexicana. mSystems, https://doi.org/10.1128/msystems.00089-21

Heat shock protein 90 (Hsp90) is a conserved molecular chaperone responsible for the folding and maturation of nascent proteins. Hsp90 is regarded as a master regulator of protein homeostasis in the cell, and its inhibition affects the functions of a... Read More about Quantitative Proteomics Reveals that Hsp90 Inhibition Dynamically Regulates Global Protein Synthesis in Leishmania mexicana.

Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase (2020)
Journal Article
Mina, J. G., Charlton, R. L., Alpizar-Sosa, E., Escrivani, D. O., Brown, C., Alqaisi, A., …Steel, P. G. (2021). Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase. ACS Infectious Diseases, 7(1), 47-63. https://doi.org/10.1021/acsinfecdis.0c00546

Current chemotherapeutics for leishmaniasis have multiple deficiencies, and there is a need for new safe, efficacious, and affordable medicines. This study describes a successful drug repurposing approach that identifies the over-the-counter antihist... Read More about Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase.

Apoptotic blebs from Leishmania major-infected macrophages as a new approach for cutaneous leishmaniasis vaccination (2020)
Journal Article
Faridnia, R., Kalani, H., Hezarjaribi, H. Z., Denny, P. W., Rafie, A., Fakhar, M., & Virgilio, S. (2020). Apoptotic blebs from Leishmania major-infected macrophages as a new approach for cutaneous leishmaniasis vaccination. Microbial Pathogenesis, 147, Article 104406. https://doi.org/10.1016/j.micpath.2020.104406

We focused on apoptotic blebs from Leishmania major-infected macrophages as a vaccine for cutaneous leishmaniasis. Apoptosis was induced in L. major-infected J774A.1 cells in order to prepare apoptotic blebs. Test groups of BALB/c mice were immunized... Read More about Apoptotic blebs from Leishmania major-infected macrophages as a new approach for cutaneous leishmaniasis vaccination.