Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle
Paola Favuzza, Manuel de Lera Ruiz, Jennifer K Thompson, Tony Triglia, Anna Ngo, Ryan WJ Steel, Marissa Vavrek, Janni Christensen, Julie Healer, Christopher Boyce, Zhuyan Guo, Mengwei Hu, Tanweer Khan, Nicholas Murgolo, Lianyun Zhao, Jocelyn Sietsma Penington, Kitsanapong Reaksudsan, Kate Jarman, Melanie H Dietrich, Lachlan Richardson Show all
Cell Host & Microbe | CELL PRESS | Published : 2020
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 i..View full abstract
Awarded by Wellcome Trust
We thank E. Loza, L. Spencer, J. Curtis, and A. Schafer for assistance with mouse experiments; the Victorian Red Cross Blood Bank for blood; and L. Dagley, T. Nebl, and A. Webb for mass spectroscopy. We acknowledge A. Stamford, B. Mckittrick, and J. Cumming for support of initial screening efforts. This work was possible through support of The Wellcome Trust [109662/Z/15/Z and 202749/Z/16/Z]; Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS; National Health and Medical Research Council of Australia.