TY - JOUR
T1 - Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle
AU - Favuzza, Paola
AU - de Lera Ruiz, Manuel
AU - Thompson, Jennifer K.
AU - Triglia, Tony
AU - Ngo, Anna
AU - Steel, Ryan W.J.
AU - Vavrek, Marissa
AU - Christensen, Janni
AU - Healer, Julie
AU - Boyce, Christopher
AU - Guo, Zhuyan
AU - Hu, Mengwei
AU - Khan, Tanweer
AU - Murgolo, Nicholas
AU - Zhao, Lianyun
AU - Penington, Jocelyn Sietsma
AU - Reaksudsan, Kitsanapong
AU - Jarman, Kate
AU - Dietrich, Melanie H.
AU - Richardson, Lachlan
AU - Guo, Kai Yuan
AU - Lopaticki, Sash
AU - Tham, Wai Hong
AU - Rottmann, Matthias
AU - Papenfuss, Tony
AU - Robbins, Jonathan A.
AU - Boddey, Justin A.
AU - Sleebs, Brad E.
AU - Sabroux, Hélène Jousset
AU - McCauley, John A.
AU - Olsen, David B.
AU - Cowman, Alan F.
N1 - Publisher Copyright:
© 2020 The Authors
PY - 2020/4/8
Y1 - 2020/4/8
N2 - 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.
AB - 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.
KW - antimalarial
KW - humanized mouse
KW - malaria
KW - merozoite
KW - plasmepsin
KW - plasmepsin IX
KW - plasmepsin X
KW - Plasmodium
UR - http://www.scopus.com/inward/record.url?scp=85080045504&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2020.02.005
DO - 10.1016/j.chom.2020.02.005
M3 - Article
C2 - 32109369
AN - SCOPUS:85080045504
SN - 1931-3128
VL - 27
SP - 642-658.e12
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 4
ER -