Medical Biology - Research Publications

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Author: Boddey, Justin × Author: Cowman, Alan × Author: Papenfuss, Anthony × Start date: 2000 × Type: Journal Article ×

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    Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle
    Favuzza, P ; Ruiz, MDL ; 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, K-Y ; Lopaticki, S ; Tham, W-H ; Rottmann, M ; Papenfuss, T ; Robbins, JA ; Boddey, JA ; Sleebs, BE ; Sabroux, HJ ; McCauley, JA ; Olsen, DB ; Cowman, AF (CELL PRESS, 2020-04-08)
    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.
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    A newly discovered protein export machine in malaria parasites
    de Koning-Ward, TF ; Gilson, PR ; Boddey, JA ; Rug, M ; Smith, BJ ; Papenfuss, AT ; Sanders, PR ; Lundie, RJ ; Maier, AG ; Cowman, AF ; Crabb, BS (NATURE PORTFOLIO, 2009-06-18)
    Several hundred malaria parasite proteins are exported beyond an encasing vacuole and into the cytosol of the host erythrocyte, a process that is central to the virulence and viability of the causative Plasmodium species. The trafficking machinery responsible for this export is unknown. Here we identify in Plasmodium falciparum a translocon of exported proteins (PTEX), which is located in the vacuole membrane. The PTEX complex is ATP-powered, and comprises heat shock protein 101 (HSP101; a ClpA/B-like ATPase from the AAA+ superfamily, of a type commonly associated with protein translocons), a novel protein termed PTEX150 and a known parasite protein, exported protein 2 (EXP2). EXP2 is the potential channel, as it is the membrane-associated component of the core PTEX complex. Two other proteins, a new protein PTEX88 and thioredoxin 2 (TRX2), were also identified as PTEX components. As a common portal for numerous crucial processes, this translocon offers a new avenue for therapeutic intervention.