Dimeric Artesunate Glycerophosphocholine Conjugate Nano-Assemblies as Slow-Release Antimalarials to Overcome Kelch 13 Mutant Artemisinin Resistance.

Autor:	Du Y; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbournegrid.1008.9, Parkville, Victoria, Australia.; School of Chemistry and Chemical Engineering, Southeast University, Nanjing, China., Giannangelo C; Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash Universitygrid.1002.3, Parkville, Victoria, Australia., He W; School of Chemistry and Chemical Engineering, Southeast University, Nanjing, China., Shami GJ; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbournegrid.1008.9, Parkville, Victoria, Australia., Zhou W; School of Chemistry and Chemical Engineering, Southeast University, Nanjing, China., Yang T; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbournegrid.1008.9, Parkville, Victoria, Australia., Creek DJ; Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash Universitygrid.1002.3, Parkville, Victoria, Australia., Dogovski C; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbournegrid.1008.9, Parkville, Victoria, Australia., Li X; School of Chemistry and Chemical Engineering, Southeast University, Nanjing, China., Tilley L; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbournegrid.1008.9, Parkville, Victoria, Australia.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2022 May 17; Vol. 66 (5), pp. e0206521. Date of Electronic Publication: 2022 Apr 13.
DOI:	10.1128/aac.02065-21
Abstrakt:	Current best practice for the treatment of malaria relies on short half-life artemisinins that are failing against emerging Kelch 13 mutant parasite strains. Here, we introduce a liposome-like self-assembly of a dimeric artesunate glycerophosphocholine conjugate (dAPC-S) as an amphiphilic prodrug for the short-lived antimalarial drug, dihydroartemisinin (DHA), with enhanced killing of Kelch 13 mutant artemisinin-resistant parasites. Cryo-electron microscopy (cryoEM) images and the dynamic light scattering (DLS) technique show that dAPC-S typically exhibits a multilamellar liposomal structure with a size distribution similar to that of the liposomes generated using thin-film dispersion (dAPC-L). Liquid chromatography-mass spectrometry (LCMS) was used to monitor the release of DHA. Sustainable release of DHA from dAPC-S and dAPC-L assemblies increased the effective dose and thus efficacy against Kelch 13 mutant artemisinin-resistant parasites in an in vitro assay. To better understand the enhanced killing effect, we investigated processes for deactivation of both the assemblies and DHA, including the roles of serum components and trace levels of iron. Analysis of parasite proteostasis pathways revealed that dAPC assemblies exert their activity via the same mechanism as DHA. We conclude that this easily prepared multilamellar liposome-like dAPC-S with long-acting efficacy shows potential for the treatment of severe and artemisinin-resistant malaria.
Databáze:	MEDLINE
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