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

Favuzza, P; de Lera Ruiz, M; Thompson, JK; Triglia, T; Ngo, A; Steel, RWJ; Vavrek, M; Christensen, J; Healer, J; Boyce, C; Guo, Z; Hu, M; Khan, T; Murgolo, N; Zhao, L; Penington, JS; Reaksudsan, K; Jarman, K; Dietrich, MH; Richardson, L; Guo, KY; Lopaticki, S; Tham, WH; Rottmann, M; Papenfuss, T; Robbins, JA; Boddey, JA; Sleebs, BE; Sabroux, HJ; McCauley, JA; Olsen, DB; Cowman, AF

Author(s): Favuzza, P; de Lera Ruiz, M; Thompson, JK; Triglia, T; Ngo, A; Steel, RWJ; Vavrek, M; Christensen, J; Healer, J; Boyce, C; Guo, Z; Hu, M; Khan, T; Murgolo, N; Zhao, L; Penington, JS; Reaksudsan, K; Jarman, K; Dietrich, MH; Richardson, L; Guo, KY; Lopaticki, S; Tham, WH; Rottmann, M; Papenfuss, T; Robbins, JA; Boddey, JA; Sleebs, BE; Sabroux, HJ; McCauley, JA; Olsen, DB; Cowman, AF;
Details: Publication Year 2020-02-27,Volume 27,Issue #4,Page 642-58 e12
Journal Title: Cell Host & Microbe
Publication Type: Journal Article
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.
Publisher: Cell Press
Research Division(s): Infectious Diseases And Immune Defence; Advanced Technology And Biology; Bioinformatics; Ubiquitin Signalling; Chemical Biology
PubMed ID: 32109369
Publisher's Version: https://doi.org/10.1016/j.chom.2020.02.005
Open Access at Publisher's Site: https://doi.org/10.1016/j.chom.2020.02.005
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2020-03-24 01:39:40

Last Modified: 2020-07-02 01:52:34