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

Autor:	Favuzza P; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia., de Lera Ruiz M; Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Thompson JK; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia., Triglia T; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia., Ngo A; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia., Steel RWJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia., Vavrek M; Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Christensen J; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia., Healer J; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia., Boyce C; Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Guo Z; Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Hu M; Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Khan T; Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Murgolo N; Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Zhao L; Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Penington JS; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia., Reaksudsan K; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia., Jarman K; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia., Dietrich MH; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia., Richardson L; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia., Guo KY; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia., Lopaticki S; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia., Tham WH; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia., Rottmann M; Swiss Tropical and Public Health Institute, Basel 4002, Switzerland., Papenfuss T; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia., Robbins JA; Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Boddey JA; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia., Sleebs BE; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia., Sabroux HJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia., McCauley JA; Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Olsen DB; Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA. Electronic address: david_olsen@merck.com., Cowman AF; 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.
Jazyk:	angličtina
Zdroj:	Cell host & microbe [Cell Host Microbe] 2020 Apr 08; Vol. 27 (4), pp. 642-658.e12. Date of Electronic Publication: 2020 Feb 27.
DOI:	10.1016/j.chom.2020.02.005
Abstrakt:	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. Competing Interests: Declaration of Interests A.F.C., M.R., P.F., Z.G., Z.L., J.M., D.B.O., B.E.S., J.K.T, T.T., and L.Z. have a patent Antimalarial Agents PCT/CN2019/100781 based on the compounds in this manuscript. (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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