2. Academic Validation
  3. Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle

Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle

  • Cell Host Microbe. 2020 Apr 8;27(4):642-658.e12. doi: 10.1016/j.chom.2020.02.005.
Paola Favuzza 1,  Manuel de Lera Ruiz 2,  Jennifer K Thompson 3,  Tony Triglia 3,  Anna Ngo 3,  Ryan W J Steel 1,  Marissa Vavrek 2,  Janni Christensen 1,  Julie Healer 1,  Christopher Boyce 2,  Zhuyan Guo 2,  Mengwei Hu 2,  Tanweer Khan 2,  Nicholas Murgolo 2,  Lianyun Zhao 2,  Jocelyn Sietsma Penington 3,  Kitsanapong Reaksudsan 1,  Kate Jarman 3,  Melanie H Dietrich 1,  Lachlan Richardson 1,  Kai-Yuan Guo 1,  Sash Lopaticki 3,  Wai-Hong Tham 1,  Matthias Rottmann 4,  Tony Papenfuss 1,  Jonathan A Robbins 2,  Justin A Boddey 1,  Brad E Sleebs 1,  Hélène Jousset Sabroux 1,  John A McCauley 2,  David B Olsen 5,  Alan F Cowman 6
Affiliations

Affiliations

  • 1 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia.
  • 2 Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
  • 3 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • 4 Swiss Tropical and Public Health Institute, Basel 4002, Switzerland.
  • 5 Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA. Electronic address: david_olsen@merck.com.
  • 6 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia. Electronic address: cowman@wehi.edu.au.
PMID: 32109369 DOI: 10.1016/j.chom.2020.02.005
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.

Keywords

Plasmodium; antimalarial; humanized mouse; malaria; merozoite; plasmepsin; plasmepsin IX; plasmepsin X.

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