Hybrid Peptide-Alkoxyamine Drugs: A Strategy for the Development of a New Family of Antiplasmodial Drugs
Ange W Embo-Ibouanga
(1)
,
Michel Nguyen
(2)
,
Lucie Paloque
(2, 3, 4)
,
Mathilde Coustets
(4)
,
Jean-Patrick Joly
(1)
,
Jean-Michel Augereau
(2, 3, 4)
,
Nicolas Vanthuyne
(5, 6, 7)
,
Raphaël Bikanga
(8)
,
Naomie Coquin
(2)
,
Anne Robert
(2)
,
Gérard Audran
(1)
,
Jérôme Boissier
(9)
,
Philippe Mellet
(10, 11)
,
Françoise Benoit-Vical
(2, 3, 4)
,
Sylvain R A Marque
(1)
1
ICR -
Institut de Chimie Radicalaire
2 LCC - Laboratoire de chimie de coordination
3 ERL1289 - New Antimalarial Molecules and Pharmacological Approaches
4 IPBS - Institut de pharmacologie et de biologie structurale
5 ECM - École Centrale de Marseille
6 AMU - Aix Marseille Université
7 ISM2 - Institut des Sciences Moléculaires de Marseille
8 USTM - Université des Sciences et Techniques de Masuku
9 IHPE - Interactions Hôtes-Pathogènes-Environnements
10 CRMSB - Centre de résonance magnétique des systèmes biologiques
11 INSERM - Institut National de la Santé et de la Recherche Médicale
2 LCC - Laboratoire de chimie de coordination
3 ERL1289 - New Antimalarial Molecules and Pharmacological Approaches
4 IPBS - Institut de pharmacologie et de biologie structurale
5 ECM - École Centrale de Marseille
6 AMU - Aix Marseille Université
7 ISM2 - Institut des Sciences Moléculaires de Marseille
8 USTM - Université des Sciences et Techniques de Masuku
9 IHPE - Interactions Hôtes-Pathogènes-Environnements
10 CRMSB - Centre de résonance magnétique des systèmes biologiques
11 INSERM - Institut National de la Santé et de la Recherche Médicale
Michel Nguyen
- Fonction : Auteur
- PersonId : 744392
- IdHAL : michel-nguyen
- ORCID : 0000-0002-6496-0495
Lucie Paloque
- Fonction : Auteur
- PersonId : 744193
- IdHAL : lucie-paloque
- ORCID : 0000-0003-0359-3959
- IdRef : 178428086
Jean-Patrick Joly
- Fonction : Auteur
- PersonId : 1365767
- IdHAL : jean-patrick-joly
- ORCID : 0000-0002-4844-7499
Jean-Michel Augereau
- Fonction : Auteur
- PersonId : 982789
- ORCID : 0000-0002-2847-1969
Nicolas Vanthuyne
- Fonction : Auteur
- PersonId : 18938
- IdHAL : nicolas-vanthuyne
- ORCID : 0000-0003-2598-7940
- IdRef : 097570222
Anne Robert
- Fonction : Auteur
- PersonId : 743927
- IdHAL : anne-robert
- ORCID : 0000-0002-9092-6776
Jérôme Boissier
- Fonction : Auteur
- PersonId : 751182
- IdHAL : jerome-boissier
- ORCID : 0000-0002-0793-3108
Françoise Benoit-Vical
- Fonction : Auteur
- PersonId : 746201
- IdHAL : francoise-benoit-vical
- ORCID : 0000-0002-9468-4823
- IdRef : 084759127
Résumé
The emergence and spread of drug-resistant Plasmodium falciparum parasites shed a serious concern on the worldwide control of malaria, the most important tropical disease in terms of mortality and morbidity. This situation has led us to consider the use of peptide-alkoxyamine derivatives as new antiplasmodial prodrugs that could potentially be efficient in the fight against resistant malaria parasites. Indeed, the peptide tag of the prodrug has been designed to be hydrolysed by parasite digestive proteases to afford highly labile alkoxyamines drugs, which spontaneously and instantaneously homolyse into two free radicals, one of which is expected to be active against P. falciparum. Since the parasite enzymes should trigger the production of the active drug in the parasite’s food vacuoles, our approach is summarized as “to dig its grave with its fork”. However, despite promising sub-micromolar IC50 values in the classical chemosensitivity assay, more in-depth tests evidenced that the anti-parasite activity of these compounds could be due to their cytostatic activity rather than a truly anti-parasitic profile, demonstrating that the antiplasmodial activity cannot be based only on measuring antiproliferative activity. It is therefore imperative to distinguish, with appropriate tests, a genuinely parasiticidal activity from a cytostatic activity.
Domaines
Sciences de l'environnementFormat du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Hybrid Peptide-Alkoxyamine Drugs: A Strategy for the Development of a New Family of Antiplasmodial Drugs
|
Résumé |
en
The emergence and spread of drug-resistant Plasmodium falciparum parasites shed a serious concern on the worldwide control of malaria, the most important tropical disease in terms of mortality and morbidity. This situation has led us to consider the use of peptide-alkoxyamine derivatives as new antiplasmodial prodrugs that could potentially be efficient in the fight against resistant malaria parasites. Indeed, the peptide tag of the prodrug has been designed to be hydrolysed by parasite digestive proteases to afford highly labile alkoxyamines drugs, which spontaneously and instantaneously homolyse into two free radicals, one of which is expected to be active against P. falciparum. Since the parasite enzymes should trigger the production of the active drug in the parasite’s food vacuoles, our approach is summarized as “to dig its grave with its fork”. However, despite promising sub-micromolar IC50 values in the classical chemosensitivity assay, more in-depth tests evidenced that the anti-parasite activity of these compounds could be due to their cytostatic activity rather than a truly anti-parasitic profile, demonstrating that the antiplasmodial activity cannot be based only on measuring antiproliferative activity. It is therefore imperative to distinguish, with appropriate tests, a genuinely parasiticidal activity from a cytostatic activity.
|
Auteur(s) |
Ange W Embo-Ibouanga
1
, Michel Nguyen
2
, Lucie Paloque
2, 3, 4
, Mathilde Coustets
4
, Jean-Patrick Joly
1
, Jean-Michel Augereau
2, 3, 4
, Nicolas Vanthuyne
5, 6, 7
, Raphaël Bikanga
8
, Naomie Coquin
2
, Anne Robert
2
, Gérard Audran
1
, Jérôme Boissier
9
, Philippe Mellet
10, 11
, Françoise Benoit-Vical
2, 3, 4
, Sylvain R A Marque
1
1
ICR -
Institut de Chimie Radicalaire
( 258556 )
- Avenue Escadrille Normandie-Niemen
Service D42
13397 Marseille cedex 20
- France
2
LCC -
Laboratoire de chimie de coordination
( 461 )
- 205 Route de Narbonne 31077 TOULOUSE CEDEX 4
- France
3
ERL1289 -
New Antimalarial Molecules and Pharmacological Approaches
( 1065633 )
- Toulouse
- France
4
IPBS -
Institut de pharmacologie et de biologie structurale
( 583 )
- 205 Route de Narbonne 31077 TOULOUSE CEDEX 4
- France
5
ECM -
École Centrale de Marseille
( 300415 )
- Pôle de l'étoile - Technopole de Château-Gombert - 38 rue Frédéric Joliot-Curie - 13013 Marseille
- France
6
AMU -
Aix Marseille Université
( 198056 )
- Aix-Marseille Université
Jardins du Pharo
58 Boulevard Charles Livon
13284 Marseille cedex 7
- France
7
ISM2 -
Institut des Sciences Moléculaires de Marseille
( 186403 )
- Campus Saint Jérôme Av. escadrille Normandie Niemen
BP 531
13397 MARSEILLE CEDEX 20
- France
8
USTM -
Université des Sciences et Techniques de Masuku
( 377466 )
- Franceville
- Gabon
9
IHPE -
Interactions Hôtes-Pathogènes-Environnements
( 1100741 )
- Université de Perpignan Via Domitia Bâtiment R 52 Avenue Paul Alduy 66860 Perpignan cedex (Languedoc-Roussillon)
- France
10
CRMSB -
Centre de résonance magnétique des systèmes biologiques
( 713 )
- Bât. A4 - case 93 146 Rue Léo Saignat 33076 BORDEAUX CEDEX
- France
11
INSERM -
Institut National de la Santé et de la Recherche Médicale
( 303623 )
- 101, rue de Tolbiac, 75013 Paris
- France
|
Langue du document |
Anglais
|
Nom de la revue |
|
Date de publication |
2024-03-21
|
Volume |
29
|
Page/Identifiant |
1397
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Audience |
Internationale
|
URL éditeur |
https://www.mdpi.com/1420-3049/29/6/1397
|
Licence |
Paternité
|
Projet(s) ANR |
|
Domaine(s) |
|
Mots-clés |
en
alkoxyamine, drug resistance, prodrug, malaria, Plasmodium
|
DOI | 10.3390/molecules29061397 |
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