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Non-Haemoglobin Degrading Plasmepsins: Drug Targets validation from Bench to Field

English title Non-Haemoglobin Degrading Plasmepsins: Drug Targets validation from Bench to Field
Applicant Soldati-Favre Dominique
Number 156825
Funding scheme Bilateral programmes
Research institution Dépt Microbiologie et Médecine Moléculaire Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Infectious Diseases
Start/End 01.04.2015 - 31.07.2018
Approved amount 246'744.00
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All Disciplines (2)

Discipline
Infectious Diseases
Medical Microbiology

Keywords (6)

Malaria; Plasmodium; Drug target identification; Aspartyl proteases; Protease inhibitors; Invasion and egress

Lay Summary (French)

Lead
La malaria demeure la plus importante maladie parasitaire dans le monde et l'une des principales menaces pour la santé humaine avec 40% de la population mondiale à risque. L'extension dramatique de la résistance du parasite à la plupart des médicaments anti-paludiques est directement responsable de la persistance généralisée de la forte incidence du paludisme et de la morbidité liée dans les régions tropicales. Nous proposons de caractériser enzymatiquement les PMIX et PMX, afin de valider de nouvelles cibles moléculaires contre le paludisme in vitro et in vivo en utilisant des isolats de terrain.
Lay summary

La malaria demeure la plus importante maladie parasitaire dans le monde et l'une des principales menaces pour la santé humaine avec 40% de la population mondiale à risque et près d’un million de décès chaque année.

Parmi les cinq espèces de Plasmodium qui infectent l’homme, P. falciparum est responsable de presque tous les décès attribués au paludisme. L'extension dramatique de la résistance du parasite à la plupart des médicaments anti-paludiques est directement responsable de la persistance généralisée de la forte incidence du paludisme et de la morbidité liée dans les régions tropicales. Il est absolument essentiel d’identifier de nouvelles cibles thérapeutiques et de développer de nouvelles molécules.

Parmi les cibles attrayantes, la voie de dégradation de l’hémoglobine qui alimente la croissance et le développement de parasites a été le centre d'attention et de recherches intensives. Plasmodium dégrade une grande part de l'hémoglobine de la cellule hôte, et en recycle les acides aminés pour la biosynthèse de ses propres protéines. Ce processus catabolique implique différentes protéases, dont des protéases aspartiques (plasmepsines I, II, IV et HAP).

Bien que les Plasmepsines impliquées dans la dégradation de l’hémoglobine ne soient pas essentielles au développement du parasite, les Plasmepsines IX et X, localisées dans les Maurer’s Clefts et au pole apical respectivement, sont essentielles à la survie du parasite. Nos résultats préliminaires sur l’analyse fonctionnelle de PMIX indiquent que cette protéase est essentielle pour l’invasion.

De plus, plusieurs molécules très actives dirigées contres la famille des Plasmepsines agissent sur les dernières étapes du cycle érythrocytaire. Notre hypothèse est que ces composés ciblent PMIX et/ou PMX. Nous proposons de valider cette hypothèse et de caractériser enzymatiquement les PMIX et PMX, afin de valider de nouvelles cibles moléculaires contre le paludisme in vitro et in vivo en utilisant des isolats de terrain.

Direct link to Lay Summary Last update: 05.03.2015

Responsible applicant and co-applicants

Employees

Project partner

Project partner

Publications

Publication
Modeling and resistant alleles explain the selectivity of antimalarial compound 49c towards apicomplexan aspartyl proteases
Mukherjee Budhaditya, Tessaro Francesca, Vahokoski Juha, Kursula Inari, Marq Jean‐Baptiste, Scapozza Leonardo, Soldati‐Favre Dominique (2018), Modeling and resistant alleles explain the selectivity of antimalarial compound 49c towards apicomplexan aspartyl proteases, in The EMBO Journal, 37(7), e98047-e98047.
A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress
Pino Paco, Caldelari Reto, Mukherjee Budhaditya, Vahokoski Juha, Klages Natacha, Maco Bohumil, Collins Christine R., Blackman Michael J., Kursula Inari, Heussler Volker, Brochet Mathieu, Soldati-Favre Dominique (2017), A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress, in Science, 358(6362), 522-528.

Collaboration

Group / person Country
Types of collaboration
Inari Kursula Finland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Volker Heussler Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Leonardo Scapozza Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
National Institute of Malaria Research India (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Molecular Approaches to Malaria Poster Plasmepsin IX and X: new candidate targets for old antimalarial drugs 21.02.2016 Lorne, Australia Soldati-Favre Dominique;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
ESAC review of MMV projects Talk 09.07.2018 Geneva MMV , Switzerland Soldati-Favre Dominique;


Communication with the public

Communication Title Media Place Year
Print (books, brochures, leaflets) La malaria, ou paludisme, est une maladie due à un parasite, un être vivant microscopique, unicell Western Switzerland 2018
Media relations: print media, online media Paludisme: nouvelle piste prometteuse Tribune de Geneve Western Switzerland 2017

Abstract

Malaria and drug-resistant forms of malaria represent the most important parasitic disease worldwide and one of the major global threat for human health with 40% of the world's population currently at risk, 300-500 million cases of clinical malaria and more than 1 million deaths each year affecting primarily the developing countries and children under the age of five. Plasmodium belongs to the phylum Apicomplexa and out of these five species P. falciparum is the most virulent and is responsible for almost all the deaths attributed to malaria. The dramatic extension of parasite resistance to most anti-malarial drugs is directly responsible for the widespread persistence of high incidence of malaria and related morbidity in tropical areas. It is absolutely critical to develop the technology for understanding comprehensively the biology of Plasmodium and the intimate relationships with its host in order to identify and validate novel arsenal of targets for intervention. Among the attractive targets, hemoglobin degrading pathway that supplies growth and development of parasites has been the focus of attention and intensive research. During its erythrocytic cycle, Plasmodium parasites degrade most of the host cell haemoglobin and recycle the amino acids for the biosynthesis of their own proteins (Goldberg, 2005). This catabolic process that takes place in the acidic food vacuole of the parasite involves a number of proteases: aspartic proteases (Plasmepsins I, II, IV and HAP), cysteine proteases (Falcipains) and metalloprotease (falcilicin) (Liu et al., 2006). While the haemoglobin degrading Plasmepsins are dispensable for parasite survival, Plasmepsins IX and X that localize to the Mauer's clefts and to the apical tip of schizonts respectively are essential for parasite survival. Preliminary data on the functional dissection of PMIX indicate that this protease is essential for egress/invasion. Importantly very potent anti-malarial drugs raised against aspartyl proteases actually act on the late step of the erythrocytic cycle and impact on parasite egress. The best of these compounds shows an IC50 of 0.6 nM (Ciana et al., 2013). We hypothesize that those compounds target either PMIX or PMX or both. We propose to challenge this hypothesis through this project that will aim to define, characterize and validate new molecular targets against malaria in vitro and in vivo using field isolates.This research project is articulated around four independent and complementary aims that can be performed in parallel. 1. Validation of Plasmespin IX and Plasmepsin X as candidate antimalarial drug targets:The conditional excision of PfPMIX gene demonstrates that this aspartyl protease is essential for parasite survival. The Swiss team will apply the same strategy to generate a Plasmodium falciparum mutant strain to conditionally disrupt the PfPMX gene. Both mutant strains will be phenotypically investigated in depth, in order to unravel the biological role and narrow down the time and site of action of these two proteases. 2. Sensitivity of PfPMIX and PfPMX to aspartly proteases inhibitors:While the hemoglobin degrading enzymes such as Plasmesin II have been extensively studied and characterized, nothing in known about PfPMIX and PfPMX, The Indian team will engage considerable efforts in exploring the heterologous expression systems with the objective of producing active proteases to perform a comprehensive biochemical and enzymatic characterization. Ultimately, the selectivity and sensitivity of these inhibition assays to different classes of aspartyl proteases inhibitors. Will be examined through enzymatic inhibition assays.3. Identification of the target (s) of hydroxy-ethyl-amine scaffolds active on late schizonts:The hydroxy-ethyl-amine scaffolds are highly potent antimalarials compounds targeting aspartyl proteases. Importantly the time of action (on late schizonts) exclude an action of haemoglobin degradation and points toward targeting PfPMIX and/ or PfPMX. To identify the drug target of these compounds, the Swiss team will i) define to precise time and mode of action by phenotyping the treated parasites and ii) use a chemistry approach to demonstrate the physical association of the lead compounds with aspartyl proeases in the parasites (in collaboration with Dr. R. Pradip, India/Seattle). 4. Evaluation of hydroxy-ethyl-amine scaffolds on field isolates and other malaria life stages and species: To establish if aspartyl proteases inhibitors targeting PfPMIX and/or PfPMX can be developed into clinically useful drugs for the treatment of malaria, the Indian team will determine the lead compounds based on hydroxy-ethyl-amine scaffolds on field isolates of malaria parasites including P. vivax.Taken together, this project covers a large panel of competences from the identification, functional characterization and validation of new molecular targets to the characterization of antimalarials compounds that presumably target them. Ultimately this project should integrate different technical approaches to meet the goal of supplying new drugs to improve the inadequate treatment options against malaria.
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