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

Du, Yawei; Giannangelo, Carlo; He, Wei; Shami, Gerald J.; Zhou, Wenxia; Yang, Tuo; Creek, Darren J.; Dogovski, Con; Li, Xinsong; Tilley, Leann

doi:10.1128/aac.02065-21

Cited by 13 publications

(21 citation statements)

References 62 publications

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“…It stimulated glycolysis, improved insulin secretion, and inhibited gluconeogenesis and adipogenesis to treat obesity. (v) Du et al (2022) introduced a liposome-like nanosystem in the self-assembly of dimeric artesunate glycerophosphocholine conjugated to the antimalarial drug dihydroartemisinin (DHA) for killing parasites. Similarly, this liposome-like nanosystem of artemisinin might induce the differentiation and decrease of regulatory cells to minimize the number of adipose cells in obesity.…”

Section: Discussionmentioning

confidence: 99%

Chinese medicinal herbs as potential prodrugs for obesity

Law

Wang²,

Lu³

et al. 2022

Front. Pharmacol.

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Obesity is a leading worldwide health threat with ever-growing prevalence, it promotes the incidence of various diseases, particularly cardiovascular disease, metabolic syndrome, diabetes, hypertension, and certain cancers. Traditional Chinese Medicine (TCM) has been used to control body weight and treat obesity for thousands of years, Chinese medicinal herbs provide a rich natural source of effective agents against obesity. However, some problems such as complex active ingredients, poor quality control, and unclear therapeutic mechanisms still need to be investigated and resolved. Prodrugs provide a path forward to overcome TCM deficiencies such as absorption, distribution, metabolism, excretion (ADME) properties, and toxicity. This article aimed to review the possible prodrugs from various medicinal plants that demonstrate beneficial effects on obesity and seek to offer insights on prodrug design as well as a solution to the global obesity issues.

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Section: Discussionmentioning

confidence: 99%

Chinese medicinal herbs as potential prodrugs for obesity

Law

Wang²,

Lu³

et al. 2022

Front. Pharmacol.

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“…To investigate PfAsnRS as a potential target, we examined the ability of OSM-S-106 to inhibit protein translation. We employed an in-cell assay of protein translation in P. falciparum trophozoites, monitored by incorporation of a clickable derivative of the puromycin homologue, O-propargylpuromycin (OPP) 14,15 . Following a 6-h exposure, protein translation is inhibited with an IC50 value of 0.51 µM (Fig.…”

Section: Osm-s-106 Inhibits Protein Translation and Induces The Amino...mentioning

confidence: 99%

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Tilley,

Xie,

Wang

et al. 2023

Preprint

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Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure activity relationship and the selectivity mechanism.

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“…The synthesis of dACC and dAPC were reported in two previous studies as anti-malaria drugs. [6,7] In this work, we employ dAPC and dACC as phospholipid and cationic lipid components with an appropriate molar ratio to first realize a stable and medicative cationic liposome (dAPC/dACC lipoplex). The classic thinfilm dispersion method was used for the lipoplex formulation (Figure 1A).…”

Section: Preparation and Physical Properties Of Dacc/dapc-dspe-peg-famentioning

confidence: 99%

“…Among them, dAPC has a more efficient assembly ability and a strong tendency to self-assemble into phospholipid bilayers, as demonstrated by our previous work. [6,7] While dACC is a cationic amphiphilic lipid providing a positive charge for electrostatic adsorption to genes. However, the self-assembly ability of dACC is not satisfied for the cationic liposomal preparation.…”

Section: Preparation and Physical Properties Of Dacc/dapc-dspe-peg-famentioning

confidence: 99%

“…They have shown significantly better therapeutic effects than the original ART in the in vitro and in vivo anti-malaria experiments. [6,7] Besides, another cationic dimeric ART-choline conjugate (dACC) prodrug for enhanced anti-malarial efficacy was reported as well, which has similar chemical structures and assembly properties to dAPC (Figure S2, Supporting Information). [8] dAPC and dACC have chemical structures similar to that of conventional phosphorylcholine as well as similar assembly capacities.…”

Section: Introductionmentioning

confidence: 99%

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Injectable Amphipathic Artesunate Prodrug‐Hydrogel Microsphere as Gene/Drug Nano‐Microplex for Rheumatoid Arthritis Therapy

et al. 2022

Adv Funct Materials

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Artemisinin and its derivatives (artemisinins) are first‐line chemotherapeutic agents of lethal malaria, which also showed tremendous value in many other diseases including chronic inflammation. Unfortunately, almost all artemisinins are rapid‐acting medicines with an extremely short half‐life in vivo, which significantly limits their clinical application for these new adaptation diseases. In this study, a locally injectable long‐acting gene/artemisinin co‐delivery nano‐microplex consisting of a biodegradable hyaluronic acid (HA) microsphere and releasable gene/artemisinin co‐delivery nano‐lipoplex is developed first, to obtain an improved efficacy for rheumatoid arthritis (RA). Briefly, a cationic multicomponent drug‐embedded liposome with pharmacological activity is first reported based on two novel artemisinin derivatives (dAPC and dACC), which possess mimic phospholipids and cationic lipids, respectively. A cationic artemisinin‐embedded lipoplex is first reported as a medicative gene carrier here. An in situ injectable TNF‐α siRNA/artemisinin co‐delivery nano‐microplex (MTAsi@MG) is further prepared by immobilization of TNF‐α siRNA/lipoplex on porous microfluidic HA microspheres. Using this nano‐microplex for intra‐articular injection, the sustaining activity of gene therapy and artemisinin efficacy for RA long‐term treatment is first realized. Undoubtedly, this intra‐articular injectable TNF‐α siRNA/artemisinin co‐delivery nano‐microplex based on dAPC/dACC lipoplex and microfluidic microspheres would be one of the most potent gene/drug co‐delivery systems for RA therapy.

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

Cited by 13 publications

References 62 publications

Chinese medicinal herbs as potential prodrugs for obesity

Chinese medicinal herbs as potential prodrugs for obesity

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Injectable Amphipathic Artesunate Prodrug‐Hydrogel Microsphere as Gene/Drug Nano‐Microplex for Rheumatoid Arthritis Therapy

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