Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle
| Autor: | Janni Christensen, David B. Olsen, Kitsanapong Reaksudsan, Jennifer K. Thompson, Kai-Yuan Guo, Wai-Hong Tham, Tony Triglia, Christopher W. Boyce, Justin A Boddey, Lianyun Zhao, Nicholas Murgolo, Marissa Vavrek, Tanweer A. Khan, Alan F. Cowman, Helene Jousset Sabroux, Jocelyn Sietsma Penington, Ryan W.J. Steel, Manuel de Lera Ruiz, Brad E. Sleebs, Jonathan A. Robbins, Zhuyan Guo, Matthias Rottmann, Paola Favuzza, Anna Ngo, Lachlan Richardson, Julie Healer, John A. Mccauley, Kate E. Jarman, Sash Lopaticki, Tony Papenfuss, Melanie H. Dietrich, Mengwei Hu |
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| Rok vydání: | 2019 |
| Předmět: |
Plasmodium
Combination therapy Plasmodium berghei Plasmodium falciparum Plasmepsin plasmepsin Mice Transgenic Pharmacology Microbiology Article 03 medical and health sciences Antimalarials Mice 0302 clinical medicine Virology parasitic diseases medicine Disease Transmission Infectious Animals Aspartic Acid Endopeptidases Parasites Antimalarial Agent plasmepsin X 030304 developmental biology 0303 health sciences Life Cycle Stages antimalarial biology Merozoites Intracellular parasite medicine.disease biology.organism_classification plasmepsin IX merozoite 3. Good health Malaria Humanized mouse Parasitology humanized mouse 030217 neurology & neurosurgery |
| Zdroj: | Cell Host & Microbe |
| ISSN: | 1934-6069 |
| Popis: | Summary 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. Graphical Abstract Highlights • Specific compounds against P. falciparum Plasmepsin IX and X were identified • PMIX and PMX are modulators of parasite proteins for egress, invasion, and development • Anti-PMIX and anti-PMX compounds inhibit liver, blood, and mosquito stages of Plasmodium • One compound, WM382, can clear mouse models of P. berghei and P. falciparum parasites We describe inhibitors of essential aspartic proteases from malaria parasites that block multiple life cycle stages. PMIX and PMX are master modulators processing proteins required for invasion, development, and egress. Administration of WM382 cured mice of malaria infection, showing that these inhibitors are promising candidates for malaria treatment and prevention. |
| Databáze: | OpenAIRE |
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