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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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.