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2. The Paradigm Shift of Using Natural Molecules Extracted from Northern Canada to Combat Malaria.

Author

Bourgeois, Alexandra, Lemos, Juliana Aline Souza, Roucheray, Stéphanie, Sergerie, Audrey, and Richard, Dave

Subjects
PARASITIC diseases, TAIGAS, MIDDLE-income countries, COMMUNICABLE diseases, MALARIA
Abstract

Parasitic diseases, such as malaria, are an immense burden to many low- and middle-income countries. In 2022, 249 million cases and 608,000 deaths were reported by the World Health Organization for malaria alone. Climate change, conflict, humanitarian crises, resource constraints and diverse biological challenges threaten progress in the elimination of malaria. Undeniably, the lack of a commercialized vaccine and the spread of drug-resistant parasites beg the need for novel approaches to treat this infectious disease. Most approaches for the development of antimalarials to date take inspiration from tropical or sub-tropical environments; however, it is necessary to expand our search. In this review, we highlight the origin of antimalarial treatments and propose new insights in the search for developing novel antiparasitic treatments. Plants and microorganisms living in harsh and cold environments, such as those found in the largely unexploited Northern Canadian boreal forest, often demonstrate interesting properties that are not found in other environments. Most prominently, the essential oil of Rhododendron tomentosum spp. Subarcticum from Nunavik and mortiamides isolated from Mortierella species found in Nunavut have shown promising activity against Plasmodium falciparum. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Chemical composition and antiplasmodial activity of the essential oil of rhododendron subarcticum leaves from Nunavik, Québec, ́Canada

Author

Séguin, Jean-Christophe, Gagnon, Dominic, Bélanger, Sarah, Richard, Dave, Fernandez, Xavier, Boudreau, Stéphane, Voyer, Normand, Séguin, Jean-Christophe, Gagnon, Dominic, Bélanger, Sarah, Richard, Dave, Fernandez, Xavier, Boudreau, Stéphane, and Voyer, Normand

Abstract

Dwarf Labrador tea, Rhododendron subarcticum Harmaja, is a popular medicinal plant in use by First Nations of Northern Canada, but its phytochemistry has remained largely unexplored. We have isolated and characterized the essential oil from a population of this species harvested near the treeline in Nunavik, Québec. Analyses by gas chromatography–mass spectrometry (GC–MS) and gas chromatography/flame-ionization detection (GC/FID) led to the identification of 53 compounds; the main secondary metabolites were ascaridole (64.7% of the total FID area) and p-cymene (21.1%). Such a composition resembles a chemotype observed for R. tomentosum, a close relative found mainly in Europe and Asia, but has never been attributed to R. subarcticum. Growth inhibition assays against different strains of Plasmodium falciparum (3D7, Dd2), the parasite responsible for the most severe form of malaria, were conducted with either the R. subarcticum’s essential oil or the isolated ascaridole. Our results show that the essential oil’s biological activity can be attributed to ascaridole as its IC50 is more than twice that of ascaridole [ascaridole’s IC50 values are 147.3 nM (3D7) and 104.9 nM (Dd2)].

Published
2023

17. A Phosphoinositide-Binding Protein Acts in the Trafficking Pathway of Hemoglobin in the Malaria Parasite Plasmodium falciparum

Author

Mukherjee, Angana, primary, Crochetière, Marie-Ève, additional, Sergerie, Audrey, additional, Amiar, Souad, additional, Thompson, L. Alexa, additional, Ebrahimzadeh, Zeinab, additional, Gagnon, Dominic, additional, Lauruol, Florian, additional, Bourgeois, Alexandra, additional, Galaup, Thomas, additional, Roucheray, Stéphanie, additional, Hallée, Stéphanie, additional, Padmanabhan, Prasad K., additional, Stahelin, Robert V., additional, Dacks, Joel B., additional, and Richard, Dave, additional

Published
2022
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18. Fragment-Based Phenotypic Lead Discovery To Identify New Drug Seeds That Target Infectious Diseases

Author

Ayotte, Yann, primary, Bernet, Eve, additional, Bilodeau, François, additional, Cimino, Mena, additional, Gagnon, Dominic, additional, Lebughe, Marthe, additional, Mistretta, Maxime, additional, Ogadinma, Paul, additional, Ouali, Sarah-Lisa, additional, Sow, Aïssatou Aïcha, additional, Chatel-Chaix, Laurent, additional, Descoteaux, Albert, additional, Manina, Giulia, additional, Richard, Dave, additional, Veyrier, Frédéric, additional, and LaPlante, Steven R., additional

Published
2021
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25. Total synthesis and antimalarial activity of mortiamides A–D

Author

Bérubé, Christopher, Gagnon, Dominic, Richard, Dave, Borgia, Alexandre, Voyer, Normand, Bérubé, Christopher, Gagnon, Dominic, Richard, Dave, Borgia, Alexandre, and Voyer, Normand

Abstract

Mortiamides A–D (1–4) are head-to-tail cyclic heptapeptides that were identified from a novel Mortierella sp. isolate obtained from marine sediments from Northern Canada. Herein we report the first total synthesis of mortiamides A–D (1–4) on a solid support by concomitant cyclization/cleavage without any oligomerization side reactions, and overall yields up to 48%. We also report on the antiplasmodial activity of mortiamides A–D (1–4). We show that three out of the four tested mortiamides (A, B and D) have moderate antiplasmodial activity, while mortiamide D (4) exhibits low micromolar activity.

Published
2020

30. Mass spectra alignment using virtual lock-masses

Author

Brochu, Francis, primary, Plante, Pier-Luc, additional, Drouin, Alexandre, additional, Gagnon, Dominic, additional, Richard, Dave, additional, Durocher, Francine, additional, Diorio, Caroline, additional, Marchand, Mario, additional, Corbeil, Jacques, additional, and Laviolette, François, additional

Published
2019
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34. Total synthesis and antimalarial activity of mortiamides A–D

Author

Bérubé, Christopher, Gagnon, Dominic, Borgia, Alexandre, Richard, Dave, Voyer, Normand, Bérubé, Christopher, Gagnon, Dominic, Borgia, Alexandre, Richard, Dave, and Voyer, Normand

Abstract

Mortiamides A–D (1–4) are head-to-tail cyclic heptapeptides that were identified from a novel Mortierella sp. isolate obtained from marine sediments from Northern Canada. Herein we report the first total synthesis of mortiamides A–D (1–4) on a solid support by concomitant cyclization/cleavage without any oligomerization side reactions, and overall yields up to 48%. We also report on the antiplasmodial activity of mortiamides A–D (1–4). We show that three out of the four tested mortiamides (A, B and D) have moderate antiplasmodial activity, while mortiamide D (4) exhibits low micromolar activity.

Published
2019

40. Mass spectra alignment using virtual lock-masses

Author

Brochu, Francis, primary, Plante, Pier-Luc, additional, Drouin, Alexandre, additional, Gagnon, Dominic, additional, Richard, Dave, additional, Durocher, Francine, additional, Diorio, Caroline, additional, Marchand, Mario, additional, Corbeil, Jacques, additional, and Laviolette, François, additional

Published
2018
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44. Export of malaria proteins requires co-translational processing of the PEXEL motif independent of phosphatidylinositol-3-phosphate binding

Author

Boddey, Justin A., O'Neill, Matthew T., Lopaticki, Sash, Carvalho, Teresa G., Hodder, Anthony N., Nebl, Thomas, Wawra, Stephan, van West, Pieter, Ebrahimzadeh, Zeinab, Richard, Dave, Flemming, Sven, Spielmann, Tobias, Przyborski, Jude, Babon, Jeff J., Cowman, Alan F., Boddey, Justin A., O'Neill, Matthew T., Lopaticki, Sash, Carvalho, Teresa G., Hodder, Anthony N., Nebl, Thomas, Wawra, Stephan, van West, Pieter, Ebrahimzadeh, Zeinab, Richard, Dave, Flemming, Sven, Spielmann, Tobias, Przyborski, Jude, Babon, Jeff J., and Cowman, Alan F.

Abstract

Plasmodium falciparum exports proteins into erythrocytes using the Plasmodium export element (PEXEL) motif, which is cleaved in the endoplasmic reticulum (ER) by plasmepsin V (PMV). A recent study reported that phosphatidylinositol-3-phosphate (PI(3)P) concentrated in the ER binds to PEXEL motifs and is required for export independent of PMV, and that PEXEL motifs are functionally interchangeable with RxLR motifs of oomycete effectors. Here we show that the PEXEL does not bind PI(3)P, and that this lipid is not concentrated in the ER. We find that RxLR motifs cannot mediate export in P. falciparum. Parasites expressing a mutated version of KAHRP, with the PEXEL motif repositioned near the signal sequence, prevented PMV cleavage. This mutant possessed the putative PI(3)P-binding residues but is not exported. Reinstatement of PEXEL to its original location restores processing by PMV and export. These results challenge the PI(3) P hypothesis and provide evidence that PEXEL position is conserved for co-translational processing and export.

Published
2016

46. The malaria parasite Plasmodium falciparum Sortilin is essential for merozoite formation and apical complex biogenesis.

Author

Hallée, Stéphanie, Counihan, Natalie A., Matthews, Kathryn, de Koning‐Ward, Tania F., and Richard, Dave

Subjects
MEROZOITES, PLASMODIUM falciparum, MITOCHONDRIA formation, ENDOPLASMIC reticulum, GENE expression, SORTILIN
Abstract

Abstract: The inner membrane complex and the apical secretory organelles are defining features of apicomplexan parasites. Despite their critical roles, the mechanisms behind the biogenesis of these structures in the malaria parasite Plasmodium falciparum are still poorly defined. We here show that decreasing expression of the P. falciparum homologue of the conserved endolysomal escorter Sortilin‐VPS10 prevents the formation of the inner membrane complex and abrogates the generation of new merozoites. Moreover, protein trafficking to the rhoptries, the micronemes, and the dense granules is disrupted, which leads to the accumulation of apical complex proteins in the endoplasmic reticulum and the parasitophorous vacuole. We further show that protein export to the erythrocyte and transport through the constitutive secretory pathway are functional. Taken together, our results suggest that the malaria parasite P. falciparum Sortilin has potentially broader functions than most of its other eukaryotic counterparts. [ABSTRACT FROM AUTHOR]

Published
2018
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47. An In vitro Co-infection Model to Study Plasmodium falciparum-HIV-1 Interactions in Human Primary Monocyte-derived Immune Cells

Author

Andreani, Guadalupe, Gagnon, Dominic, Lodge, Robert, Tremblay, Michel J., and Richard, Dave

Subjects
Issue 66, Monocyte-Derived Macrophages, Erythrocytes, Co-infections, Coinfection, Macrophages, Immunology, PBMC, Plasmodium falciparum, HIV Infections, Dendritic Cells, Red blood cells, Virus Replication, Malaria, AIDS, parasitic diseases, HIV-1, Leukocytes, Mononuclear, Medicine, Humans, Parasites, Malaria, Falciparum, Infection
Abstract

Plasmodium falciparum, the causative agent of the deadliest form of malaria, and human immunodeficiency virus type-1 (HIV-1) are among the most important health problems worldwide, being responsible for a total of 4 million deaths annually1. Due to their extensive overlap in developing regions, especially Sub-Saharan Africa, co-infections with malaria and HIV-1 are common, but the interplay between the two diseases is poorly understood. Epidemiological reports have suggested that malarial infection transiently enhances HIV-1 replication and increases HIV-1 viral load in co-infected individuals2,3. Because this viremia stays high for several weeks after treatment with antimalarials, this phenomenon could have an impact on disease progression and transmission. The cellular immunological mechanisms behind these observations have been studied only scarcely. The few in vitro studies investigating the impact of malaria on HIV-1 have demonstrated that exposure to soluble malarial antigens can increase HIV-1 infection and reactivation in immune cells. However, these studies used whole cell extracts of P. falciparum schizont stage parasites and peripheral blood mononuclear cells (PBMC), making it hard to decipher which malarial component(s) was responsible for the observed effects and what the target host cells were4,5. Recent work has demonstrated that exposure of immature monocyte-derived dendritic cells to the malarial pigment hemozoin increased their ability to transfer HIV-1 to CD4+ T cells6,7, but that it decreased HIV-1 infection of macrophages8. To shed light on this complex process, a systematic analysis of the interactions between the malaria parasite and HIV-1 in different relevant human primary cell populations is critically needed. Several techniques for investigating the impact of HIV-1 on the phagocytosis of micro-organisms and the effect of such pathogens on HIV-1 replication have been described. We here present a method to investigate the effects of P. falciparum-infected erythrocytes on the replication of HIV-1 in human primary monocyte-derived macrophages. The impact of parasite exposure on HIV-1 transcriptional/translational events is monitored by using single cycle pseudotyped viruses in which a luciferase reporter gene has replaced the Env gene while the effect on the quantity of virus released by the infected macrophages is determined by measuring the HIV-1 capsid protein p24 by ELISA in cell supernatants.

Published
2012

48. Export of malaria proteins requires co-translational processing of the PEXEL motif independent of phosphatidylinositol-3-phosphate binding

Author

Boddey, Justin A., primary, O’Neill, Matthew T., additional, Lopaticki, Sash, additional, Carvalho, Teresa G., additional, Hodder, Anthony N., additional, Nebl, Thomas, additional, Wawra, Stephan, additional, van West, Pieter, additional, Ebrahimzadeh, Zeinab, additional, Richard, Dave, additional, Flemming, Sven, additional, Spielmann, Tobias, additional, Przyborski, Jude, additional, Babon, Jeff J., additional, and Cowman, Alan F., additional

Published
2016
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