Skip to main content

Research Repository

Advanced Search

Outputs (67)

Evaluation of the Leishmania inositol phosphorylceramide synthase as a drug target using a chemical and genetic approach (2024)
Journal Article
Denny, P. (online). Evaluation of the Leishmania inositol phosphorylceramide synthase as a drug target using a chemical and genetic approach. ACS Infectious Diseases,

The lack of effective vaccines and the development of resistance to the current treatments highlights the urgent need for new antileishmanials. Sphingolipid metabolism has been proposed as a promising source of Leishmania-specific targets as these li... 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.

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.

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. (2021). 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.

An investigation of the antileishmanial properties of semi-synthetic saponins (2020)
Journal Article
Anderson, O., Beckett, J., Briggs, C., Natrass, L., Cranston, C., Wilkinson, E., …Denny, P. (2020). An investigation of the antileishmanial properties of semi-synthetic saponins. RSC Medicinal Chemistry, 11(7), 833-842. https://doi.org/10.1039/d0md00123f

Leishmaniasis is a neglected tropical disease caused by insect-vector borne protozoan parasites of the, Leishmania species. Whilst infection threatens and affects millions of the global poor, vaccines are absent and drug therapy limited. Extensive ef... Read More about An investigation of the antileishmanial properties of semi-synthetic saponins.

A BONCAT-iTRAQ method enables temporally resolved quantitative profiling of newly synthesised proteins in Leishmania mexicana parasites during starvation (2019)
Journal Article
Karunakaran, K., & Denny, P. W. (2019). A BONCAT-iTRAQ method enables temporally resolved quantitative profiling of newly synthesised proteins in Leishmania mexicana parasites during starvation. PLoS Neglected Tropical Diseases, 13(12), Article e0007651. https://doi.org/10.1371/journal.pntd.0007651

Adaptation to starvation is integral to the Leishmania life cycle. The parasite can survive prolonged periods of nutrient deprivation both in vitro and in vivo. The identification of parasite proteins synthesised during starvation is key to unravelli... Read More about A BONCAT-iTRAQ method enables temporally resolved quantitative profiling of newly synthesised proteins in Leishmania mexicana parasites during starvation.

Mining for natural product antileishmanials in a fungal extract library (2019)
Journal Article
Mbekeani, A., Jones, R., Bassas Llorens, M., Elliot, J., Regnault, C., Barrett, M., …Denny, P. (2019). Mining for natural product antileishmanials in a fungal extract library. International Journal for Parasitology: Drugs and Drug Resistance, 11, 118-128. https://doi.org/10.1016/j.ijpddr.2019.05.003

Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the World's poorest, however vaccines are absent and drug therapy limited. Recently, public-private... Read More about Mining for natural product antileishmanials in a fungal extract library.

The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity (2019)
Journal Article
Pinneh, E., Mina, J., Stark, M., Lindell, S., Luemmen, P., Knight, M., …Denny, P. (2019). The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity. Scientific Reports, 9, Article 8083. https://doi.org/10.1038/s41598-019-44544-1

Resistance to 157 different herbicides and 88% of known sites of action has been observed, with many weeds resistant to two or more modes. Coupled with tighter environmental regulation, this demonstrates the need to identify new modes of action and n... Read More about The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity.

Expression levels of inositol phosphorylceramide synthase modulate plant responses to biotic and abiotic stress in Arabidopsis thaliana (2019)
Journal Article
Pinneh, E., Stoppel, R., Knight, H., Knight, M., Steel, P., & Denny, P. (2019). Expression levels of inositol phosphorylceramide synthase modulate plant responses to biotic and abiotic stress in Arabidopsis thaliana. PLoS ONE, 14(5), Article e0217087. https://doi.org/10.1371/journal.pone.0217087

This research was undertaken to investigate the global role of the plant inositol phosphorylceramide synthase (IPCS), a non-mammalian enzyme previously shown to be associated with the pathogen response. RNA-Seq analyses demonstrated that over-express... Read More about Expression levels of inositol phosphorylceramide synthase modulate plant responses to biotic and abiotic stress in Arabidopsis thaliana.

Lytic reactions of drugs with lipid membranes (2018)
Journal Article
Britt, H. M., García-Herrero, C. A., Denny, P. W., Mosely, J. A., & Sanderson, J. M. (2019). Lytic reactions of drugs with lipid membranes. Chemical Science, 10(3), 674-680. https://doi.org/10.1039/c8sc04831b

Propranolol is shown to undergo lipidation reactions in three types of lipid membrane: (1) synthetic single-component glycerophospholipid liposomes; (2) liposomes formed from complex lipid mixtures extracted from E. coli or liver cells; and (3) in ce... Read More about Lytic reactions of drugs with lipid membranes.

Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania (2018)
Journal Article
Trinconi, C. T., Miguel, D. C., Silber, A. M., Brown, C., Mina, J. G., Denny, P. W., …Uliana, S. R. (2018). Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania. International Journal for Parasitology: Drugs and Drug Resistance, 8(3), 475-487. https://doi.org/10.1016/j.ijpddr.2018.10.007

Previous work from our group showed that tamoxifen, an oral drug that has been in use for the treatment of breast cancer for over 40 years, is active both in vitro and in vivo against several species of Leishmania, the etiological agent of leishmania... Read More about Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania.

Yeast: bridging the gap between phenotypic and biochemical assays for high-throughput screening (2018)
Journal Article
Denny, P. W. (2018). Yeast: bridging the gap between phenotypic and biochemical assays for high-throughput screening. Expert Opinion on Drug Discovery, 13(12), 1153-1160. https://doi.org/10.1080/17460441.2018.1534826

Introduction: Both in vitro biochemical and phenotypic assay platforms have clear limitations in high throughput screening (HTS) for drug discovery. The use of genetically tractable model yeast as a vehicle for target-based HTS overcomes many of thes... Read More about Yeast: bridging the gap between phenotypic and biochemical assays for high-throughput screening.

Functional analyses of a putative, membrane-bound, peroxisomal import mechanism from the apicomplexan protozoan Toxoplasma gondii (2018)
Journal Article
Mbekeani, A., Stanley, W., Kalel, V., Dohan, N., Zalckvar, E., Scheiner, L., …Denny, P. (2018). Functional analyses of a putative, membrane-bound, peroxisomal import mechanism from the apicomplexan protozoan Toxoplasma gondii. Genes, 9(9), Article 434. https://doi.org/10.3390/genes9090434

Peroxisomes are central to eukaryotic metabolism, including the oxidation of fatty acids—which subsequently provide an important source of metabolic energy—and in the biosynthesis of cholesterol and plasmalogens. However, the presence and nature of p... Read More about Functional analyses of a putative, membrane-bound, peroxisomal import mechanism from the apicomplexan protozoan Toxoplasma gondii.

Identifying inhibitors of the Leishmania inositol phosphorylceramide synthase with antiprotozoal activity using a yeast-based assay and ultra-high throughput screening platform (2018)
Journal Article
Norcliffe, J., Mina, J., Alvarez-Ruiz, E., Cantizani-Perez, J., de Dios-Anton, F., Colmenarejo, G., …Denny, P. (2018). Identifying inhibitors of the Leishmania inositol phosphorylceramide synthase with antiprotozoal activity using a yeast-based assay and ultra-high throughput screening platform. Scientific Reports, 8, Article 3938. https://doi.org/10.1038/s41598-018-22063-9

Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the world’s poorest, however vaccines are absent and drug therapy limited. Recently, public-private... Read More about Identifying inhibitors of the Leishmania inositol phosphorylceramide synthase with antiprotozoal activity using a yeast-based assay and ultra-high throughput screening platform.

A complex interplay between sphingolipid and sterol metabolism revealed by perturbations to the Leishmania metabolome caused by miltefosine (2018)
Journal Article
Armitage, E., Alqaisi, A., Godzien, J., Pena, I., Mbekeani, A., Alsonso-Herranz, V., …Barbas, C. (2018). A complex interplay between sphingolipid and sterol metabolism revealed by perturbations to the Leishmania metabolome caused by miltefosine. Antimicrobial Agents and Chemotherapy, 62(5), e02095-17. https://doi.org/10.1128/aac.02095-17

With the World Health Organization reporting over 30,000 deaths and 200-400,000 new cases annually, visceral Leishmaniasis is a serious disease affecting some of the world's poorest people. As drug resistance continues to rise, there is a huge unmet... Read More about A complex interplay between sphingolipid and sterol metabolism revealed by perturbations to the Leishmania metabolome caused by miltefosine.

Microbial protein targets: towards understanding and intervention (2017)
Journal Article
Denny, P. (2018). Microbial protein targets: towards understanding and intervention. Parasitology, 145(2), 111-115. https://doi.org/10.1017/s0031182017002037

The rise of antimicrobial resistance, coupled with a lack of industrial focus on antimicrobial discovery over preceding decades, has brought the world to a crisis point. With both human and animal health set to decline due to increased disease burden... Read More about Microbial protein targets: towards understanding and intervention.

Repurposing as a Strategy for the Discovery of New Anti-Leishmanials: The-State-of-the-Art (2017)
Journal Article
Charlton, R., Rossi-Bergmann, B., Denny, P. W., & Steel, P. G. (2018). Repurposing as a Strategy for the Discovery of New Anti-Leishmanials: The-State-of-the-Art. Parasitology, 145(2), 219-236. https://doi.org/10.1017/s0031182017000993

Leishmaniasis is a vector-borne neglected tropical disease caused by protozoan parasites of the genus Leishmania for which there is a paucity of effective viable non-toxic drugs. There are 1·3 million new cases each year causing considerable socio-ec... Read More about Repurposing as a Strategy for the Discovery of New Anti-Leishmanials: The-State-of-the-Art.

Everybody needs sphingolipids, right! Mining for new drug targets in protozoan sphingolipid biosynthesis (2017)
Journal Article
Mina, J., & Denny, P. (2018). Everybody needs sphingolipids, right! Mining for new drug targets in protozoan sphingolipid biosynthesis. Parasitology, 145(2), 134-147. https://doi.org/10.1017/s0031182017001081

Sphingolipids (SLs) are an integral part of all eukaryotic cellular membranes. In addition, they have indispensable functions as signalling molecules controlling a myriad of cellular events. Disruption of either the de novo synthesis or the degradati... Read More about Everybody needs sphingolipids, right! Mining for new drug targets in protozoan sphingolipid biosynthesis.

Functional and phylogenetic evidence of a bacterial origin for the first enzyme in sphingolipid biosynthesis in a phylum of eukaryotic protozoan parasites (2017)
Journal Article
Mina, J., Thye, J., Alqaisi, A., Bird, L., Dods, R., Groftehauge, M., …Denny, P. W. (2017). Functional and phylogenetic evidence of a bacterial origin for the first enzyme in sphingolipid biosynthesis in a phylum of eukaryotic protozoan parasites. Journal of Biological Chemistry, 292(29), 12208-12219. https://doi.org/10.1074/jbc.m117.792374

Toxoplasma gondii is an obligate, intracellular eukaryotic apicomplexan protozoan parasite that can cause fetal damage and abortion in both animals and humans. Sphingolipids are essential and ubiquitous components of eukaryotic membranes that are bot... Read More about Functional and phylogenetic evidence of a bacterial origin for the first enzyme in sphingolipid biosynthesis in a phylum of eukaryotic protozoan parasites.

The antifungal Aureobasidin A and an analogue are active against the protozoan parasite Toxoplasma gondii but do not inhibit sphingolipid biosynthesis (2017)
Journal Article
Alqaisi, A., Mbekeani, A., Bassas Llorens, M., Elhammer, A., & Denny, P. (2018). The antifungal Aureobasidin A and an analogue are active against the protozoan parasite Toxoplasma gondii but do not inhibit sphingolipid biosynthesis. Parasitology, 145(2), 148-155. https://doi.org/10.1017/s0031182017000506

Toxoplasma gondii is an obligate intracellular protozoan parasite of the phylum Apicomplexa, and toxoplasmosis is an important disease of both humans and economically important animals. With a limited array of drugs available there is a need to ident... Read More about The antifungal Aureobasidin A and an analogue are active against the protozoan parasite Toxoplasma gondii but do not inhibit sphingolipid biosynthesis.

An Efficient Method for the Synthesis of Peptoids with Mixed Lysine-type/Arginine-type Monomers and Evaluation of Their Anti-leishmanial Activity (2016)
Journal Article
Bolt, H., Denny, P., & Cobb, S. (2016). An Efficient Method for the Synthesis of Peptoids with Mixed Lysine-type/Arginine-type Monomers and Evaluation of Their Anti-leishmanial Activity. Journal of Visualized Experiments, 117, Article e54750. https://doi.org/10.3791/54750

This protocol describes the manual solid-phase synthesis of linear peptoids that contain two differently functionalized cationic monomers. In this procedure amino functionalized 'lysine' and guanido functionalized 'arginine' peptoid monomers can be i... Read More about An Efficient Method for the Synthesis of Peptoids with Mixed Lysine-type/Arginine-type Monomers and Evaluation of Their Anti-leishmanial Activity.

Enlarging the chemical space of anti-leishmanials: a structure-activity relationship study of peptoids against Leishmania mexicana, a causative agent of cutaneous leishmaniasis (2016)
Journal Article
Bolt, H., Eggimann, G., Denny, P., & Cobb, S. (2016). Enlarging the chemical space of anti-leishmanials: a structure-activity relationship study of peptoids against Leishmania mexicana, a causative agent of cutaneous leishmaniasis. MedChemComm, 7(5), 799-805. https://doi.org/10.1039/c6md00060f

Peptoids, a class of peptide mimetics, have emerged as promising anti-infective agents against a range of bacterial and fungal infections. Recently we have shown peptoids to be novel anti-parasitic and, specifically, anti-leishmanial, compounds. In t... Read More about Enlarging the chemical space of anti-leishmanials: a structure-activity relationship study of peptoids against Leishmania mexicana, a causative agent of cutaneous leishmaniasis.

Crystal Structure of a Hidden Protein, YcaC, a Putative Cysteine Hydrolase from Pseudomonas aeruginosa, with and without an Acrylamide Adduct (2015)
Journal Article
Grøftehauge, M., Truan, D., Vasil, A., Denny, P., Vasil, M., & Pohl, E. (2015). Crystal Structure of a Hidden Protein, YcaC, a Putative Cysteine Hydrolase from Pseudomonas aeruginosa, with and without an Acrylamide Adduct. International Journal of Molecular Sciences, 16(7), 15971-15984. https://doi.org/10.3390/ijms160715971

As part of the ongoing effort to functionally and structurally characterize virulence factors in the opportunistic pathogen Pseudomonas aeruginosa, we determined the crystal structure of YcaC co-purified with the target protein at resolutions of 2.34... Read More about Crystal Structure of a Hidden Protein, YcaC, a Putative Cysteine Hydrolase from Pseudomonas aeruginosa, with and without an Acrylamide Adduct.

The Role of Phosphoglycans in the Susceptibility of Leishmania mexicana to the Temporin Family of Anti-Microbial Peptides (2015)
Journal Article
Eggimann, G., Sweeney, K., Bolt, H., Rozatian, N., Cobb, S., & Denny, P. (2015). The Role of Phosphoglycans in the Susceptibility of Leishmania mexicana to the Temporin Family of Anti-Microbial Peptides. Molecules, 20(2), 2775-2785. https://doi.org/10.3390/molecules20022775

Natural product antimicrobial peptides (AMPs) have been proposed as promising agents against the Leishmania species, insect vector borne protozoan parasites causing the neglected tropical disease leishmaniasis. However, recent studies have shown that... Read More about The Role of Phosphoglycans in the Susceptibility of Leishmania mexicana to the Temporin Family of Anti-Microbial Peptides.

Investigating the Anti-leishmanial Effects of Linear Peptoids (2014)
Journal Article
Eggimann, G., Bolt, H., Denny, P., & Cobb, S. (2015). Investigating the Anti-leishmanial Effects of Linear Peptoids. ChemMedChem, 10(3), 233-237. https://doi.org/10.1002/cmdc.201402416

Peptoids, a class of peptide mimetics, have emerged as promising anti-infective agents against a range of bacterial infections. Herein we present the first study of the antiparasitic and specifically the anti-leishmanial properties of linear peptoids... Read More about Investigating the Anti-leishmanial Effects of Linear Peptoids.

Yeast as a Potential Vehicle for Neglected Tropical Disease Drug Discovery (2014)
Journal Article
Denny, P., & Steel, P. (2015). Yeast as a Potential Vehicle for Neglected Tropical Disease Drug Discovery. Journal of biomolecular screening, 20(1), 56-63. https://doi.org/10.1177/1087057114546552

High-throughput screening (HTS) efforts for neglected tropical disease (NTD) drug discovery have recently received increased attention because several initiatives have begun to attempt to reduce the deficit in new and clinically acceptable therapies... Read More about Yeast as a Potential Vehicle for Neglected Tropical Disease Drug Discovery.

The utility of yeast as a tool for cell-based, target-directed high-throughput screening (2014)
Journal Article
Norcliffe, J., Alvarez-Ruiz, E., Martin-Plaza, J., Steel, P., & Denny, P. (2014). The utility of yeast as a tool for cell-based, target-directed high-throughput screening. Parasitology, 141(1), 8-16. https://doi.org/10.1017/s0031182013000425

Many Neglected Tropical Diseases (NTDs) have recently been subject of increased focus, particularly with relation to high-throughput screening (HTS) initiatives. These vital endeavours largely rely of two approaches, in vitro target-directed screenin... Read More about The utility of yeast as a tool for cell-based, target-directed high-throughput screening.

Sphingolipid synthesis and scavenging in the intracellular apicomplexan parasite, Toxoplasma gondii (2013)
Journal Article
Pratt, S., Wansadhipathi-Kannangara, N., Bruce, C., Mina, J., Shams-Eldin, H., Casas, J., …Denny, P. (2013). Sphingolipid synthesis and scavenging in the intracellular apicomplexan parasite, Toxoplasma gondii. Molecular and Biochemical Parasitology, 87(1), 43-51. https://doi.org/10.1016/j.molbiopara.2012.11.007

Sphingolipids are essential components of eukaryotic cell membranes, particularly the plasma membrane, and are involved in a diverse array of signal transduction pathways. Mammals produce sphingomyelin (SM) as the primary complex sphingolipid via the... Read More about Sphingolipid synthesis and scavenging in the intracellular apicomplexan parasite, Toxoplasma gondii.

Aqueous synthesis of N,S,-dialkylthiophosphoramidates: design, optimisation and application to library construction and antileishmanial testing (2013)
Journal Article
Trmčić, M., Chadbourne, F., Brear, P., Denny, P., Cobb, S., & Hodgson, D. (2013). Aqueous synthesis of N,S,-dialkylthiophosphoramidates: design, optimisation and application to library construction and antileishmanial testing. Organic and Biomolecular Chemistry, 11(16), 2660-2675. https://doi.org/10.1039/c3ob27448a

We recently reported the use of PSCl3 for the thiophosphorylation of alkylamines where the resulting N-thiophosphoramidate ions could be readily S-alkylated (Chem. Commun., 2011, 47, 6156–6158.). Herein we report the development of this methodology u... Read More about Aqueous synthesis of N,S,-dialkylthiophosphoramidates: design, optimisation and application to library construction and antileishmanial testing.

Lipid Metabolism as a Therapeutic Target (Editorial) (2012)
Journal Article
Smith, T., Reynolds, T., & Denny, P. (2012). Lipid Metabolism as a Therapeutic Target (Editorial). Biochemistry Research International, 2012, Article 158139. https://doi.org/10.1155/2012/158139

Targeting lipid metabolism (biosynthesis and catabolism) associated with human diseases and pathogens with therapeutics has gained much momentum in recent years. This has come about in part due to the wide availability of sequenced genomes, the advan... Read More about Lipid Metabolism as a Therapeutic Target (Editorial).

Sphingolipid and ceramide homeostasis, potential therapeutic targets (2012)
Journal Article
Young, S., Mina, J., Denny, P., & Smith, T. (2012). Sphingolipid and ceramide homeostasis, potential therapeutic targets. Biochemistry Research International, 2012, Article 248135. https://doi.org/10.1155/2012/248135

Sphingolipids are ubiquitous in eukaryotic cells where they have been attributed a plethora of functions from the formation of structural domains to polarized cellular trafficking and signal transduction. Recent research has identified and characteri... Read More about Sphingolipid and ceramide homeostasis, potential therapeutic targets.

Endocytosis and sphingolipid scavenging in Leishmania mexicana amastigotes (2011)
Journal Article
Ali, H., Harding, C., & Denny, P. (2012). Endocytosis and sphingolipid scavenging in Leishmania mexicana amastigotes. Biochemistry Research International, 2012, Article 691363. https://doi.org/10.1155/2012/691363

Leishmania species are the causative agents of the leishmaniases, a spectrum of neglected tropical diseases. Amastigote stage parasites exist within macrophages and scavenge host factors for survival, for example, Leishmania species utilise host sphi... Read More about Endocytosis and sphingolipid scavenging in Leishmania mexicana amastigotes.

Studies on the antileishmanial properties of the antimicrobial peptides temporin A, B and 1Sa (2011)
Journal Article
Chadbourne, F., Raleigh, C., Ali, H., Denny, P., & Cobb, S. (2011). Studies on the antileishmanial properties of the antimicrobial peptides temporin A, B and 1Sa. Journal of Peptide Science, 17(11), 751-755. https://doi.org/10.1002/psc.1398

Given the paucity and toxicity of available drugs for leishmaniasis, coupled with the advent of drug resistance, the discovery of new therapies for this neglected tropical disease is recognised as being of the utmost urgency. As such antimicrobial pe... Read More about Studies on the antileishmanial properties of the antimicrobial peptides temporin A, B and 1Sa.

Exploring Leishmania major inositol phosphorylceramide synthase (LmjIPCS): insights into the ceramide binding domain (2011)
Journal Article
Mina, J., Mosely, J., Ali, H., Denny, P., & Steel, P. (2011). Exploring Leishmania major inositol phosphorylceramide synthase (LmjIPCS): insights into the ceramide binding domain. Organic and Biomolecular Chemistry, 9(6), 1823-1830. https://doi.org/10.1039/c0ob00871k

The synthesis of set of ceramide analogues exploring hydrophobicity in the acyl chains and the degree and nature of hydroxylation is described. These have been assayed against the parasitic protozoan enzyme LmjIPCS. These studies showed that whilst t... Read More about Exploring Leishmania major inositol phosphorylceramide synthase (LmjIPCS): insights into the ceramide binding domain.

Antimicrobial peptides for leishmaniasis (2010)
Journal Article
Cobb, S., & Denny, P. (2010). Antimicrobial peptides for leishmaniasis. Current opinion in investigational drugs, 11(8), 868-875

Leishmaniasis is a parasitic disease that is endemic to American, African, Asian and southern European countries. More than 350 million individuals in 88 countries are at risk of infection from this neglected tropical disease. No effective vaccinatio... Read More about Antimicrobial peptides for leishmaniasis.

A plate-based assay system for analyses and screening of the Leishmania major inositol phosphorylceramide synthase (2010)
Journal Article
Mina, J., Mosely, J., Ali, H., Shams-Eldin, H., Schwarz, R., Steel, P., & Denny, P. (2010). A plate-based assay system for analyses and screening of the Leishmania major inositol phosphorylceramide synthase. International Journal of Biochemistry and Cell Biology, 42(9), 1553-1561. https://doi.org/10.1016/j.biocel.2010.06.008

Sphingolipids are key components of eukaryotic membranes, particularly the plasma membrane. The biosynthetic pathway for the formation of these lipid species is largely conserved. However, in contrast to mammals, which produce sphingomyelin, organism... Read More about A plate-based assay system for analyses and screening of the Leishmania major inositol phosphorylceramide synthase.

Functional analyses of differentially expressed isoforms of the Arabidopsis inositol phosphorylceramide synthase (2010)
Journal Article
Mina, J., Okada, Y., Wansadhipathi-Kannangara, N., Pratt, S., Shams-Eldin, H., Schwarz, R., …Denny, P. (2010). Functional analyses of differentially expressed isoforms of the Arabidopsis inositol phosphorylceramide synthase. Plant Molecular Biology, 73(4-5), 399-407. https://doi.org/10.1007/s11103-010-9626-3

Sphingolipids are key components of eukaryotic plasma membranes that are involved in many functions, including the formation signal transduction complexes. In addition, these lipid species and their catabolites function as secondary signalling molecu... Read More about Functional analyses of differentially expressed isoforms of the Arabidopsis inositol phosphorylceramide synthase.

The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target (2009)
Journal Article
Mina, J., Pan, S., Wansadhipathi, N., Bruce, C., Shams-Eldin, H., Schwarz, R., …Denny, P. (2009). The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target. Molecular and Biochemical Parasitology, 168(1), 16-23. https://doi.org/10.1016/j.molbiopara.2009.06.002

Sphingolipids are important components of eukaryotic membranes, particularly the plasma membrane, and are involved in a diverse array of signal transduction processes. In the Eukaryota the biosynthetic pathway for the formation of these lipid species... Read More about The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target.

The protozoan inositol phosphorylceramide synthase: A novel drug target that defines a new class of sphingolipid synthase (2006)
Journal Article
Denny, P., Shams-Eldin, H., Price, H., Smith, D., & Schwarz, R. (2006). The protozoan inositol phosphorylceramide synthase: A novel drug target that defines a new class of sphingolipid synthase. Journal of Biological Chemistry, 281(38), 28200-28209. https://doi.org/10.1074/jbc.m600796200

Sphingolipids are ubiquitous and essential components of eukaryotic membranes, particularly the plasma membrane. The biosynthetic pathway for the formation of these lipid species is conserved up to the formation of sphinganine. However, a divergence... Read More about The protozoan inositol phosphorylceramide synthase: A novel drug target that defines a new class of sphingolipid synthase.

An evolutionarily conserved coiled-coil protein implicated in polycystic kidney disease is involved in basal body duplication and flagellar biogenesis in Trypanosoma brucei (2005)
Journal Article
Morgan, G., Denny, P., Vaughan, S., Goulding, D., Jeffries, T., Smith, D., …Field, M. (2005). An evolutionarily conserved coiled-coil protein implicated in polycystic kidney disease is involved in basal body duplication and flagellar biogenesis in Trypanosoma brucei. Molecular and Cellular Biology, 25(9), 3774-3783. https://doi.org/10.1128/mcb.25.9.3774-3783.2005

Trypanosoma brucei is a flagellated protozoan with a highly polarized cellular structure. TbLRTP is a trypanosomal protein containing multiple SDS22-class leucine-rich repeats and a coiled-coil domain with high similarity to a mammalian testis-specif... Read More about An evolutionarily conserved coiled-coil protein implicated in polycystic kidney disease is involved in basal body duplication and flagellar biogenesis in Trypanosoma brucei.

Direct transport across the plasma membrane of mammalian cells of Leishmania HASPB as revealed by a CHO export mutant (2005)
Journal Article
Stegmayer, C., Kehlenbach, A., Tournaviti, S., Wegehingel, S., Zehe, C., Denny, P., …Nickel, W. (2005). Direct transport across the plasma membrane of mammalian cells of Leishmania HASPB as revealed by a CHO export mutant. Journal of Cell Science, 118(3), 517-527. https://doi.org/10.1242/jcs.01645

Leishmania HASPB is a lipoprotein that is exported to the extracellular space from both Leishmania parasites and mammalian cells via an unconventional secretory pathway. Exported HASPB remains anchored in the outer leaflet of the plasma membrane medi... Read More about Direct transport across the plasma membrane of mammalian cells of Leishmania HASPB as revealed by a CHO export mutant.

Leishmania major: clathrin and adaptin complexes of an intra-cellular parasite (2005)
Journal Article
Denny, P., Morgan, G., Field, M., & Smith, D. (2005). Leishmania major: clathrin and adaptin complexes of an intra-cellular parasite. Experimental Parasitology, 109(1), 33-37. https://doi.org/10.1016/j.exppara.2004.10.007

To investigate the role of clathrin-mediated trafficking during the Leishmania lifecycle, open reading frames encoding clathrin heavy chain and the β-adaptins, major components of the adaptor complexes, have been analysed both in silico and experimen... Read More about Leishmania major: clathrin and adaptin complexes of an intra-cellular parasite.

Rafts and sphingolipid biosynthesis in the kinetoplastid parasitic protozoa (2004)
Journal Article
Denny, P., & Smith, D. (2004). Rafts and sphingolipid biosynthesis in the kinetoplastid parasitic protozoa. Molecular Microbiology, 53(3), 725-733. https://doi.org/10.1111/j.1365-2958.2004.04208.x

Although the concept of eukaryotic lipid rafts arouses controversy, recent biophysical studies strongly indicate that inducible, stable and relatively large rafts are a feature of activated mammalian cells. These studies allow us to consider the func... Read More about Rafts and sphingolipid biosynthesis in the kinetoplastid parasitic protozoa.

Sphingolipid-free Leishmania are defective in membrane trafficking, differentiation and infectivity (2004)
Journal Article
Denny, P., Goulding, D., Ferguson, M., & Smith, D. (2004). Sphingolipid-free Leishmania are defective in membrane trafficking, differentiation and infectivity. Molecular Microbiology, 52(2), 313-327. https://doi.org/10.1111/j.1365-2958.2003.03975.x

Sphingolipids are structural components of the eukaryotic plasma membrane that are involved, together with cholesterol, in the formation of lipid microdomains (rafts). Additionally, sphingolipid metabolites have been shown to modulate a wide variety... Read More about Sphingolipid-free Leishmania are defective in membrane trafficking, differentiation and infectivity.

Ether phospholipids and glycosylinositolphospholipids are not required for amastigote virulence or for inhibition of macrophage activation by Leishmania major (2003)
Journal Article
Zufferey, R., Allen, S., Barron, T., Sullivan, D., Denny, P., Almeida, I., …Beverley, S. (2003). Ether phospholipids and glycosylinositolphospholipids are not required for amastigote virulence or for inhibition of macrophage activation by Leishmania major. Journal of Biological Chemistry, 278(45), 44708-44718. https://doi.org/10.1074/jbc.m308063200

Ether phospholipids are major components of the membranes of humans and Leishmania. In protozoan parasites they occur separately or as part of the glycosylphosphatidylinositol (GPI) anchor of molecules implicated in virulence, such as lipophosphoglyc... Read More about Ether phospholipids and glycosylinositolphospholipids are not required for amastigote virulence or for inhibition of macrophage activation by Leishmania major.

The endocytic apparatus of the kinetoplastida. Part II: machinery and components of the system (2002)
Journal Article
Morgan, G., Hall, B., Denny, P., Field, M., & Carrington, M. (2002). The endocytic apparatus of the kinetoplastida. Part II: machinery and components of the system. Trends in Parasitology, 18(12), 540-546. https://doi.org/10.1016/s1471-4922%2802%2902392-9

Endocytic systems within eukaryotic cells are a diverse set of intracellular transport pathways responsible for uptake, recycling, interaction with the exocytic system and degradation of molecules. Each of these pathways requires the interaction of d... Read More about The endocytic apparatus of the kinetoplastida. Part II: machinery and components of the system.

The kinetoplastida endocytic apparatus. Part I: a dynamic system for nutrition and evasion of host defences (2002)
Journal Article
Morgan, G., Hall, B., Denny, P., Carrington, M., & Field, M. (2002). The kinetoplastida endocytic apparatus. Part I: a dynamic system for nutrition and evasion of host defences. Trends in Parasitology, 18(11), 491-496. https://doi.org/10.1016/s1471-4922%2802%2902391-7

The endocytic system of kinetoplastid parasites is a highly polarized membrane network focused on the flagellar pocket localized at one end of the cell. When first characterized, the endosomal network was envisioned as a simple system for uptake of e... Read More about The kinetoplastida endocytic apparatus. Part I: a dynamic system for nutrition and evasion of host defences.

Leishmania RAB7: characterisation of terminal endocytic stages in an intracellular parasite (2002)
Journal Article
Denny, P., Lewis, S., Tempero, J., Goulding, D., Ivens, A., Field, M., & Smith, D. (2002). Leishmania RAB7: characterisation of terminal endocytic stages in an intracellular parasite. Molecular and Biochemical Parasitology, 123(2), 105-113. https://doi.org/10.1016/s0166-6851%2802%2900133-0

Leishmania species are intracellular parasites that inhabit a parasitophorous vacuole (PV) within host macrophages and engage with the host endo-membrane network to avoid clearance from the cell. Intracellular Leishmania amastigotes exhibit a high de... Read More about Leishmania RAB7: characterisation of terminal endocytic stages in an intracellular parasite.

Phenotypic changes associated with deletion and overexpression of a stage-regulated gene family in Leishmania (2001)
Journal Article
McKean, P., Denny, P., Knuepfer, E., Keen, J., & Smith, D. (2001). Phenotypic changes associated with deletion and overexpression of a stage-regulated gene family in Leishmania. Cellular Microbiology, 3(8), 511-523. https://doi.org/10.1046/j.1462-5822.2001.00135.x

The LmcDNA16 locus of Leishmania major contains three highly related genes HASPA1, HASPA2 and HASPB, encoding hydrophilic, acylated surface proteins and a tandem pair of unrelated sequences, SHERP1 and SHERP2, coding for a small, hydrophilic protein... Read More about Phenotypic changes associated with deletion and overexpression of a stage-regulated gene family in Leishmania.

GPI-anchored proteins and glycoconjugates segregate into lipid rafts in Kinetoplastida (2001)
Journal Article
Denny, P., Field, M., & Smith, D. (2001). GPI-anchored proteins and glycoconjugates segregate into lipid rafts in Kinetoplastida. FEBS Letters, 491(1-2), 148-153. https://doi.org/10.1016/s0014-5793%2801%2902172-x

The plasma membranes of the divergent eukaryotic parasites, Leishmania and Trypanosoma, are highly specialised, with a thick coat of glycoconjugates and glycoproteins playing a central role in virulence. Unusually, the majority of these surface macro... Read More about GPI-anchored proteins and glycoconjugates segregate into lipid rafts in Kinetoplastida.

The in vivo conformation of the Plastid DNA of Toxoplasma gondii: Implications for replication (2001)
Journal Article
Williamson, D., Denny, P., Moore, P., Sato, S., McCready, S., & Wilson, R. (2001). The in vivo conformation of the Plastid DNA of Toxoplasma gondii: Implications for replication. Journal of Molecular Biology, 306(2), 159-168. https://doi.org/10.1006/jmbi.2000.4385

The Phylum Apicomplexa comprises thousands of obligate intracellular parasites, some of which cause serious disease in man and other animals. Though not photosynthetic, some of them, including the malaria parasites (Plasmodium spp.) and the causative... Read More about The in vivo conformation of the Plastid DNA of Toxoplasma gondii: Implications for replication.