Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantum
Summary: Antileishmanial chemotherapy is currently limited due to severe toxic side effects and drug resistance. Hence, new antileishmanial compounds based on alternative approaches, mainly to avoid the emergence of drug resistance, are needed. The present work aims to decipher the mechanism of acti...
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| 格式: | 文件 |
| 语言: | English |
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Elsevier
2023-11-01
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| 丛编: | iScience |
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| 在线阅读: | http://www.sciencedirect.com/science/article/pii/S2589004223022216 |
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| author | Sameh Obeid Eloisa Berbel-Manaia Valérie Nicolas Indira Dennemont Julien Barbier Jean-Christophe Cintrat Daniel Gillet Philippe M. Loiseau Sébastien Pomel |
| author_facet | Sameh Obeid Eloisa Berbel-Manaia Valérie Nicolas Indira Dennemont Julien Barbier Jean-Christophe Cintrat Daniel Gillet Philippe M. Loiseau Sébastien Pomel |
| author_sort | Sameh Obeid |
| collection | DOAJ |
| description | Summary: Antileishmanial chemotherapy is currently limited due to severe toxic side effects and drug resistance. Hence, new antileishmanial compounds based on alternative approaches, mainly to avoid the emergence of drug resistance, are needed. The present work aims to decipher the mechanism of action of an antileishmanial drug candidate, named VP343, inhibiting intracellular Leishmania infantum survival via the host cell. Cell imaging showed that VP343 interferes with the fusion of parasitophorous vacuoles and host cell late endosomes and lysosomes, leading to lysosomal cholesterol accumulation and ROS overproduction within host cells. Proteomic analyses showed that VP343 perturbs host cell vesicular trafficking as well as cholesterol synthesis/transport pathways. Furthermore, a knockdown of two selected targets involved in vesicle-mediated transport, Pik3c3 and Sirt2, resulted in similar antileishmanial activity to VP343 treatment. This work revealed potential host cell pathways and targets altered by VP343 that would be of interest for further development of host-directed antileishmanial drugs. |
| first_indexed | 2024-03-11T17:03:42Z |
| format | Article |
| id | doaj.art-dbcda9f2fa5048c280c47e5708a19e5b |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-11T17:03:42Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-dbcda9f2fa5048c280c47e5708a19e5b2023-10-20T06:48:24ZengElsevieriScience2589-00422023-11-012611108144Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantumSameh Obeid0Eloisa Berbel-Manaia1Valérie Nicolas2Indira Dennemont3Julien Barbier4Jean-Christophe Cintrat5Daniel Gillet6Philippe M. Loiseau7Sébastien Pomel8Université Paris-Saclay, CNRS BioCIS, 91400 Orsay, FranceUniversité Paris-Saclay, CNRS BioCIS, 91400 Orsay, FranceUniversité Paris-Saclay, UMS-IPSIT, Microscopy Facility, 92019 Châtenay-Malabry, FranceUniversité Paris-Saclay, CNRS BioCIS, 91400 Orsay, FranceUniversité Paris-Saclay, UMS-IPSIT, Microscopy Facility, 92019 Châtenay-Malabry, FranceUniversité Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SCBM, 91191 Gif-sur-Yvette, FranceUniversité Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SIMoS, 91191 Gif-sur-Yvette, FranceUniversité Paris-Saclay, CNRS BioCIS, 91400 Orsay, FranceUniversité Paris-Saclay, CNRS BioCIS, 91400 Orsay, France; Corresponding authorSummary: Antileishmanial chemotherapy is currently limited due to severe toxic side effects and drug resistance. Hence, new antileishmanial compounds based on alternative approaches, mainly to avoid the emergence of drug resistance, are needed. The present work aims to decipher the mechanism of action of an antileishmanial drug candidate, named VP343, inhibiting intracellular Leishmania infantum survival via the host cell. Cell imaging showed that VP343 interferes with the fusion of parasitophorous vacuoles and host cell late endosomes and lysosomes, leading to lysosomal cholesterol accumulation and ROS overproduction within host cells. Proteomic analyses showed that VP343 perturbs host cell vesicular trafficking as well as cholesterol synthesis/transport pathways. Furthermore, a knockdown of two selected targets involved in vesicle-mediated transport, Pik3c3 and Sirt2, resulted in similar antileishmanial activity to VP343 treatment. This work revealed potential host cell pathways and targets altered by VP343 that would be of interest for further development of host-directed antileishmanial drugs.http://www.sciencedirect.com/science/article/pii/S2589004223022216ParasitologyDrugsCell biology |
| spellingShingle | Sameh Obeid Eloisa Berbel-Manaia Valérie Nicolas Indira Dennemont Julien Barbier Jean-Christophe Cintrat Daniel Gillet Philippe M. Loiseau Sébastien Pomel Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantum iScience Parasitology Drugs Cell biology |
| title | Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantum |
| title_full | Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantum |
| title_fullStr | Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantum |
| title_full_unstemmed | Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantum |
| title_short | Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantum |
| title_sort | deciphering the mechanism of action of vp343 an antileishmanial drug candidate in leishmania infantum |
| topic | Parasitology Drugs Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223022216 |
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