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Dual plasmepsin-targeting antimalarial agents disrupt multiple stages of the malaria parasite life cycle

Favuzza, Paola and de Lera Ruiz, Manuel and Thompson, Jennifer K. and Triglia, Tony and Ngo, Anna and Steel, Ryan W. J. and Vavrek, Marissa and Christensen, Janni and Healer, Julie and Boyce, Christopher and Guo, Zhuyan and Hu, Mengwei and Khan, Tanweer and Murgolo, Nicholas and Zhao, Lianyun and Penington, Jocelyn Sietsma and Reaksudsan, Kitsanapong and Jarman, Kate and Dietrich, Melanie H. and Richardson, Lachlan and Guo, Kai-Yuan and Lopaticki, Sash and Tham, Wai-Hong and Rottmann, Matthias and Papenfuss, Tony and Robbins, Jonathan A. and Boddey, Justin A. and Sleebs, Brad E. and Sabroux, Hélène Jousset and McCauley, John A. and Olsen, David B. and Cowman, Alan F.. (2020) Dual plasmepsin-targeting antimalarial agents disrupt multiple stages of the malaria parasite life cycle. Cell host & microbe, 27 (4). pp. 642-658.e12.

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Official URL: https://edoc.unibas.ch/76444/

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Abstract

Artemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium. However, increased resistance to ACT highlights the importance of finding new drugs. Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets. In this study, we describe dual inhibitors of PMIX and PMX, including WM382, that block multiple stages of the Plasmodium life cycle. We demonstrate that PMX is a master modulator of merozoite invasion and direct maturation of proteins required for invasion, parasite development, and egress. Oral administration of WM382 cured mice of P. berghei and prevented blood infection from the liver. In addition, WM382 was efficacious against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes. Selection of resistant P. falciparum in vitro was not achievable. Together, these show that dual PMIX and PMX inhibitors are promising candidates for malaria treatment and prevention.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Rottmann, Matthias
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
ISSN:1931-3128
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:23 Apr 2020 14:48
Deposited On:23 Apr 2020 14:48

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