Author: Sleebs, Brad E. ; McCauley, John A. ; Robbins, Johnathan ; Hu, Bin ; Boddey, Justin ; Zhao, Lianyun ; Thompson, Jennifer ; Ngo, Anna ; Favuzza, Paola ; Guo, Zhuyan ; Zhan, Dongmei ; Olsen, David B. ; Murgolo, Nicholas ; Lowes, Kym N. ; Jarman, Kate E. ; de Lera Ruiz, Manuel ; Cowman, Alan F. ; Boyce, Christopher W. ; Lei, Zhiyu ; Vavrek, Marissa

Drug resistance to first-line antimalarials-including artemisinin-is increasing, resulting in a critical need for the discovery of new agents with novel mechanisms of action. In collaboration with the Walter and Eliza Hall Institute and with funding from the Wellcome Trust, a phenotypic screen of Merck's aspartyl protease inhibitor library identified a series of plasmepsin X (PMX) hits that were more potent than chloroquine. Inspired by a PMX homology model, efforts to optimize the potency resulted in the discovery of leads that, in addition to potently inhibiting PMX, also inhibit another essential aspartic protease, plasmepsin IX (PMIX). Further potency and pharmacokinetic profile optimization efforts culminated in the discovery of WM382, a very potent dual PMIX/X inhibitor with robust in vivo efficacy at multiple stages of the malaria parasite life cycle and an excellent resistance profile.

01 Jul 2022·StructureQ2 · BIOLOGY

Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax

Q2 · BIOLOGY

Article

Author: McCauley, John A ; Christensen, Janni ; Triglia, Tony ; Hodder, Anthony N ; Murgolo, Nicholas ; Guo, Zhuyan ; Cowman, Alan F ; Lowes, Kym ; Scally, Stephen ; Ngo, Anna ; Czabotar, Peter E ; Lera Ruiz, Manuel de ; Bailey, Brodie ; Sleebs, Brad E ; Tham, Wai-Hong ; Favuzza, Paola ; Dietrich, Melanie H ; Birkinshaw, Richard W ; Olsen, David

Plasmepsins IX (PMIX) and X (PMX) are essential aspartyl proteases for Plasmodium spp. egress, invasion, and development. WM4 and WM382 inhibit PMIX and PMX in Plasmodium falciparum and P. vivax. WM4 inhibits PMX, while WM382 is a dual inhibitor of PMIX and PMX. To understand their function, we identified protein substrates. Enzyme kinetic and structural analyses identified interactions responsible for drug specificity. PMIX and PMX have similar substrate specificity; however, there are distinct differences for peptide and protein substrates. Differences in WM4 and WM382 binding for PMIX and PMX map to variations in the S' region and engagement of the active site S3 pocket. Structures of PMX reveal interactions and mechanistic detail of drug binding important for development of clinical candidates against these targets.

01 Apr 2020·Cell Host & Microbe

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

Article

Author: Rottmann, Matthias ; Thompson, Jennifer K ; Olsen, David B ; Khan, Tanweer ; Sleebs, Brad E ; Cowman, Alan F ; Guo, Zhuyan ; Papenfuss, Tony ; Penington, Jocelyn Sietsma ; Sabroux, Hélène Jousset ; Dietrich, Melanie H ; Boddey, Justin A ; McCauley, John A ; Vavrek, Marissa ; Ngo, Anna ; de Lera Ruiz, Manuel ; Robbins, Jonathan A ; Jarman, Kate ; Triglia, Tony ; Richardson, Lachlan ; Zhao, Lianyun ; Boyce, Christopher ; Favuzza, Paola ; Hu, Mengwei ; Healer, Julie ; Guo, Kai-Yuan ; Reaksudsan, Kitsanapong ; Steel, Ryan W J ; Murgolo, Nicholas ; Christensen, Janni ; Lopaticki, Sash ; Tham, Wai-Hong

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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Indication	Highest Phase	Country/Location	Organization	Date
Malaria	Preclinical	Australia	The Walter & Eliza Hall Institute of Medical Research	-
Malaria	Preclinical	United States	Merck AG	-
Malaria, Falciparum	Discovery	United States	Merck & Co., Inc.	25 Oct 2019
Malaria, Falciparum	Discovery	United States	The Walter & Eliza Hall Institute of Medical Research	25 Oct 2019
Plasmodium knowlesi infection	Discovery	United States	Merck & Co., Inc.	25 Oct 2019
Plasmodium knowlesi infection	Discovery	United States	The Walter & Eliza Hall Institute of Medical Research	25 Oct 2019

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