The Experts below are selected from a list of 297 Experts worldwide ranked by ideXlab platform
Darren J Creek - One of the best experts on this subject based on the ideXlab platform.
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system wide biochemical analysis reveals Ozonide antimalarials initially act by disrupting plasmodium falciparum haemoglobin digestion
PLOS Pathogens, 2020Co-Authors: Carlo Giannangelo, Susan A Charman, Ghizal Siddiqui, Amanda De Paoli, Bethany M Anderson, Laura E Edgingtonmitchell, Darren J CreekAbstract:Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a "multi-omics" workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of Ozonide-treated P. falciparum infected red blood cells revealed a rapid depletion of short Hb-derived peptides followed by subsequent alterations in lipid and nucleotide metabolism, while untargeted peptidomics showed accumulation of longer Hb-derived peptides. Quantitative proteomics and ABPP assays demonstrated that Hb-digesting proteases were increased in abundance and activity following treatment, respectively. Ozonide-induced depletion of short Hb-derived peptides was less extensive in a drug-treated K13-mutant artemisinin resistant parasite line (Cam3.IIR539T) than in the drug-treated isogenic sensitive strain (Cam3.IIrev), further confirming the association between Ozonide activity and Hb catabolism. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in Ozonide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short Ozonide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate Ozonide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage Ozonide-induced damage.
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system wide biochemical analysis reveals Ozonide antimalarials initially act by disrupting plasmodium falciparum haemoglobin digestion
bioRxiv, 2020Co-Authors: Carlo Giannangelo, Susan A Charman, Ghizal Siddiqui, Amanda De Paoli, Bethany M Anderson, Laura E Edgingtonmitchell, Darren J CreekAbstract:Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum . Here we used a “multi-omics” workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of Ozonide-treated P. falciparum infected red blood cells revealed a rapid depletion of short Hb-derived peptides followed by subsequent alterations in lipid and nucleotide metabolism, while untargeted peptidomics showed accumulation of longer Hb-derived peptides. Quantitative proteomics and ABPP assays demonstrated that Hb-digesting proteases were increased in abundance and activity following treatment, respectively. The association between Ozonide activity and Hb catabolism was also confirmed in a K13 -mutant artemisinin resistant parasite line. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in Ozonide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short Ozonide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate Ozonide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage Ozonide-induced damage.
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Ozonide antimalarials alkylate heme in the malaria parasite plasmodium falciparum
ACS Infectious Diseases, 2019Co-Authors: Carlo Giannangelo, Jonathan L Vennerstrom, Xiaofang Wang, Susan A Charman, Dovile Anderson, Darren J CreekAbstract:The mechanism of action of Ozonide antimalarials involves activation by intraparasitic iron and the formation of highly reactive carbon-centered radicals that alkylate malaria parasite proteins. Given free intraparasitic heme is generally thought to be the iron source responsible for Ozonide activation and its likely close proximity to the activated drug, we investigated heme as a possible molecular target of the Ozonides. Using an extraction method optimized for solubilization of free heme, untargeted LC-MS analysis of Ozonide-treated parasites identified several regioisomers of Ozonide-alkylated heme, which resulted from covalent modification of the heme porphyrin ring by an Ozonide-derived carbon-centered radical. In addition to the intact alkylated heme adduct, putative Ozonide-alkylated heme degradation products were also detected. This study directly demonstrates Ozonide modification of heme within the malaria parasite Plasmodium falciparum, revealing that this process may be important for the biological activity of Ozonide antimalarials.
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Ozonide antimalarial activity in the context of artemisinin resistant malaria
Trends in Parasitology, 2019Co-Authors: Carlo Giannangelo, Freya J I Fowkes, Julie A Simpson, Susan A Charman, Darren J CreekAbstract:The Ozonides are one of the most advanced drug classes in the antimalarial development pipeline and were designed to improve on limitations associated with current front-line artemisinin-based therapies. Like the artemisinins, the pharmacophoric peroxide bond of Ozonides is essential for activity, and it appears that these antimalarials share a similar mode of action, raising the possibility of cross-resistance. Resistance to artemisinins is associated with Plasmodium falciparum mutations that allow resistant parasites to escape short-term artemisinin-mediated damage (elimination half-life ~1 h). Importantly, some Ozonides (e.g., OZ439) have a sustained in vivo drug exposure profile, providing a major pharmacokinetic advantage over the artemisinin derivatives. Here, we describe recent progress made towards understanding Ozonide antimalarial activity and discuss Ozonide utility within the context of artemisinin resistance.
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parasite mediated degradation of synthetic Ozonide antimalarials impacts in vitro antimalarial activity
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Carlo Giannangelo, Susan A Charman, Tuo Yang, Leann Tilley, Lukas Stingelin, Darren J CreekAbstract:The peroxide bond of the artemisinins inspired the development of a class of fully synthetic 1,2,4-trioxolane-based antimalarials, collectively known as the Ozonides. Similar to the artemisinins, heme-mediated degradation of the Ozonides generates highly reactive radical species that are thought to mediate parasite killing by damaging critical parasite biomolecules. We examined the relationship between parasite dependent degradation and antimalarial activity for two Ozonides, OZ277 (arterolane) and OZ439 (artefenomel), using a combination of in vitro drug stability and pulsed-exposure activity assays. Our results showed that drug degradation is parasite stage dependent and positively correlates with parasite load. Increasing trophozoite-stage parasitemia leads to substantially higher rates of degradation for both OZ277 and OZ439, and this is associated with a reduction in in vitro antimalarial activity. Under conditions of very high parasitemia (∼90%), OZ277 and OZ439 were rapidly degraded and completely devoid of activity in trophozoite-stage parasite cultures exposed to a 3-h drug pulse. This study highlights the impact of increasing parasite load on Ozonide stability and in vitro antimalarial activity and should be considered when investigating the antimalarial mode of action of the Ozonide antimalarials under conditions of high parasitemia.
Susan A Charman - One of the best experts on this subject based on the ideXlab platform.
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system wide biochemical analysis reveals Ozonide antimalarials initially act by disrupting plasmodium falciparum haemoglobin digestion
PLOS Pathogens, 2020Co-Authors: Carlo Giannangelo, Susan A Charman, Ghizal Siddiqui, Amanda De Paoli, Bethany M Anderson, Laura E Edgingtonmitchell, Darren J CreekAbstract:Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a "multi-omics" workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of Ozonide-treated P. falciparum infected red blood cells revealed a rapid depletion of short Hb-derived peptides followed by subsequent alterations in lipid and nucleotide metabolism, while untargeted peptidomics showed accumulation of longer Hb-derived peptides. Quantitative proteomics and ABPP assays demonstrated that Hb-digesting proteases were increased in abundance and activity following treatment, respectively. Ozonide-induced depletion of short Hb-derived peptides was less extensive in a drug-treated K13-mutant artemisinin resistant parasite line (Cam3.IIR539T) than in the drug-treated isogenic sensitive strain (Cam3.IIrev), further confirming the association between Ozonide activity and Hb catabolism. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in Ozonide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short Ozonide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate Ozonide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage Ozonide-induced damage.
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system wide biochemical analysis reveals Ozonide antimalarials initially act by disrupting plasmodium falciparum haemoglobin digestion
bioRxiv, 2020Co-Authors: Carlo Giannangelo, Susan A Charman, Ghizal Siddiqui, Amanda De Paoli, Bethany M Anderson, Laura E Edgingtonmitchell, Darren J CreekAbstract:Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum . Here we used a “multi-omics” workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of Ozonide-treated P. falciparum infected red blood cells revealed a rapid depletion of short Hb-derived peptides followed by subsequent alterations in lipid and nucleotide metabolism, while untargeted peptidomics showed accumulation of longer Hb-derived peptides. Quantitative proteomics and ABPP assays demonstrated that Hb-digesting proteases were increased in abundance and activity following treatment, respectively. The association between Ozonide activity and Hb catabolism was also confirmed in a K13 -mutant artemisinin resistant parasite line. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in Ozonide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short Ozonide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate Ozonide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage Ozonide-induced damage.
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Ozonide antimalarials alkylate heme in the malaria parasite plasmodium falciparum
ACS Infectious Diseases, 2019Co-Authors: Carlo Giannangelo, Jonathan L Vennerstrom, Xiaofang Wang, Susan A Charman, Dovile Anderson, Darren J CreekAbstract:The mechanism of action of Ozonide antimalarials involves activation by intraparasitic iron and the formation of highly reactive carbon-centered radicals that alkylate malaria parasite proteins. Given free intraparasitic heme is generally thought to be the iron source responsible for Ozonide activation and its likely close proximity to the activated drug, we investigated heme as a possible molecular target of the Ozonides. Using an extraction method optimized for solubilization of free heme, untargeted LC-MS analysis of Ozonide-treated parasites identified several regioisomers of Ozonide-alkylated heme, which resulted from covalent modification of the heme porphyrin ring by an Ozonide-derived carbon-centered radical. In addition to the intact alkylated heme adduct, putative Ozonide-alkylated heme degradation products were also detected. This study directly demonstrates Ozonide modification of heme within the malaria parasite Plasmodium falciparum, revealing that this process may be important for the biological activity of Ozonide antimalarials.
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Ozonide antimalarial activity in the context of artemisinin resistant malaria
Trends in Parasitology, 2019Co-Authors: Carlo Giannangelo, Freya J I Fowkes, Julie A Simpson, Susan A Charman, Darren J CreekAbstract:The Ozonides are one of the most advanced drug classes in the antimalarial development pipeline and were designed to improve on limitations associated with current front-line artemisinin-based therapies. Like the artemisinins, the pharmacophoric peroxide bond of Ozonides is essential for activity, and it appears that these antimalarials share a similar mode of action, raising the possibility of cross-resistance. Resistance to artemisinins is associated with Plasmodium falciparum mutations that allow resistant parasites to escape short-term artemisinin-mediated damage (elimination half-life ~1 h). Importantly, some Ozonides (e.g., OZ439) have a sustained in vivo drug exposure profile, providing a major pharmacokinetic advantage over the artemisinin derivatives. Here, we describe recent progress made towards understanding Ozonide antimalarial activity and discuss Ozonide utility within the context of artemisinin resistance.
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parasite mediated degradation of synthetic Ozonide antimalarials impacts in vitro antimalarial activity
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Carlo Giannangelo, Susan A Charman, Tuo Yang, Leann Tilley, Lukas Stingelin, Darren J CreekAbstract:The peroxide bond of the artemisinins inspired the development of a class of fully synthetic 1,2,4-trioxolane-based antimalarials, collectively known as the Ozonides. Similar to the artemisinins, heme-mediated degradation of the Ozonides generates highly reactive radical species that are thought to mediate parasite killing by damaging critical parasite biomolecules. We examined the relationship between parasite dependent degradation and antimalarial activity for two Ozonides, OZ277 (arterolane) and OZ439 (artefenomel), using a combination of in vitro drug stability and pulsed-exposure activity assays. Our results showed that drug degradation is parasite stage dependent and positively correlates with parasite load. Increasing trophozoite-stage parasitemia leads to substantially higher rates of degradation for both OZ277 and OZ439, and this is associated with a reduction in in vitro antimalarial activity. Under conditions of very high parasitemia (∼90%), OZ277 and OZ439 were rapidly degraded and completely devoid of activity in trophozoite-stage parasite cultures exposed to a 3-h drug pulse. This study highlights the impact of increasing parasite load on Ozonide stability and in vitro antimalarial activity and should be considered when investigating the antimalarial mode of action of the Ozonide antimalarials under conditions of high parasitemia.
Carlo Giannangelo - One of the best experts on this subject based on the ideXlab platform.
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system wide biochemical analysis reveals Ozonide antimalarials initially act by disrupting plasmodium falciparum haemoglobin digestion
PLOS Pathogens, 2020Co-Authors: Carlo Giannangelo, Susan A Charman, Ghizal Siddiqui, Amanda De Paoli, Bethany M Anderson, Laura E Edgingtonmitchell, Darren J CreekAbstract:Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a "multi-omics" workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of Ozonide-treated P. falciparum infected red blood cells revealed a rapid depletion of short Hb-derived peptides followed by subsequent alterations in lipid and nucleotide metabolism, while untargeted peptidomics showed accumulation of longer Hb-derived peptides. Quantitative proteomics and ABPP assays demonstrated that Hb-digesting proteases were increased in abundance and activity following treatment, respectively. Ozonide-induced depletion of short Hb-derived peptides was less extensive in a drug-treated K13-mutant artemisinin resistant parasite line (Cam3.IIR539T) than in the drug-treated isogenic sensitive strain (Cam3.IIrev), further confirming the association between Ozonide activity and Hb catabolism. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in Ozonide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short Ozonide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate Ozonide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage Ozonide-induced damage.
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system wide biochemical analysis reveals Ozonide antimalarials initially act by disrupting plasmodium falciparum haemoglobin digestion
bioRxiv, 2020Co-Authors: Carlo Giannangelo, Susan A Charman, Ghizal Siddiqui, Amanda De Paoli, Bethany M Anderson, Laura E Edgingtonmitchell, Darren J CreekAbstract:Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum . Here we used a “multi-omics” workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of Ozonide-treated P. falciparum infected red blood cells revealed a rapid depletion of short Hb-derived peptides followed by subsequent alterations in lipid and nucleotide metabolism, while untargeted peptidomics showed accumulation of longer Hb-derived peptides. Quantitative proteomics and ABPP assays demonstrated that Hb-digesting proteases were increased in abundance and activity following treatment, respectively. The association between Ozonide activity and Hb catabolism was also confirmed in a K13 -mutant artemisinin resistant parasite line. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in Ozonide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short Ozonide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate Ozonide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage Ozonide-induced damage.
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Ozonide antimalarials alkylate heme in the malaria parasite plasmodium falciparum
ACS Infectious Diseases, 2019Co-Authors: Carlo Giannangelo, Jonathan L Vennerstrom, Xiaofang Wang, Susan A Charman, Dovile Anderson, Darren J CreekAbstract:The mechanism of action of Ozonide antimalarials involves activation by intraparasitic iron and the formation of highly reactive carbon-centered radicals that alkylate malaria parasite proteins. Given free intraparasitic heme is generally thought to be the iron source responsible for Ozonide activation and its likely close proximity to the activated drug, we investigated heme as a possible molecular target of the Ozonides. Using an extraction method optimized for solubilization of free heme, untargeted LC-MS analysis of Ozonide-treated parasites identified several regioisomers of Ozonide-alkylated heme, which resulted from covalent modification of the heme porphyrin ring by an Ozonide-derived carbon-centered radical. In addition to the intact alkylated heme adduct, putative Ozonide-alkylated heme degradation products were also detected. This study directly demonstrates Ozonide modification of heme within the malaria parasite Plasmodium falciparum, revealing that this process may be important for the biological activity of Ozonide antimalarials.
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Ozonide antimalarial activity in the context of artemisinin resistant malaria
Trends in Parasitology, 2019Co-Authors: Carlo Giannangelo, Freya J I Fowkes, Julie A Simpson, Susan A Charman, Darren J CreekAbstract:The Ozonides are one of the most advanced drug classes in the antimalarial development pipeline and were designed to improve on limitations associated with current front-line artemisinin-based therapies. Like the artemisinins, the pharmacophoric peroxide bond of Ozonides is essential for activity, and it appears that these antimalarials share a similar mode of action, raising the possibility of cross-resistance. Resistance to artemisinins is associated with Plasmodium falciparum mutations that allow resistant parasites to escape short-term artemisinin-mediated damage (elimination half-life ~1 h). Importantly, some Ozonides (e.g., OZ439) have a sustained in vivo drug exposure profile, providing a major pharmacokinetic advantage over the artemisinin derivatives. Here, we describe recent progress made towards understanding Ozonide antimalarial activity and discuss Ozonide utility within the context of artemisinin resistance.
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Biochemical pathways and molecular targets involved in the mechanism of action of Ozonide antimalarials in Plasmodium falciparum
2018Co-Authors: Carlo GiannangeloAbstract:This thesis examined the mechanism of action of new medicines for malaria, known as Ozonides. Many malaria deaths are caused by multi-drug resistant parasites that can escape the effect of current malaria medicines. This thesis identified that the parasite haemoglobin digestion pathway plays a central role in the mechanisms of action and resistance of Ozonide antimalarials. This detailed mechanistic understanding will facilitate further development and clinical utilisation of Ozonides by allowing rational selection of partner drugs and monitoring for resistance
Yuxiang Dong - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationship of antischistosomal Ozonide carboxylic acids
Journal of Medicinal Chemistry, 2020Co-Authors: Xiaofang Wang, Sriraghavan Kamaraj, Vivek J Bulbule, Francis C K Chiu, Cecile Haberli, David M Shackleford, Eileen Ryan, Alexander I Wallick, Yuxiang DongAbstract:Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal Ozonide carboxylic acids OZ418 (2) and OZ165 (3). Irrespective of lipophilicity, these Ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.
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structure activity relationship of the antimalarial Ozonide artefenomel oz439
Journal of Medicinal Chemistry, 2017Co-Authors: Yuxiang Dong, Xiaofang Wang, Sriraghavan Kamaraj, Vivek J Bulbule, Francis C K Chiu, Jacques Chollet, Manickam Dhanasekaran, Christopher D HeinAbstract:Building on insights gained from the discovery of the antimalarial Ozonide arterolane (OZ277), we now describe the structure–activity relationship (SAR) of the antimalarial Ozonide artefenomel (OZ439). Primary and secondary amino Ozonides had higher metabolic stabilities than tertiary amino Ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino Ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino Ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino Ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino Ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these Ozonides was most often associ...
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Structure–Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439)
2017Co-Authors: Yuxiang Dong, Xiaofang Wang, Sriraghavan Kamaraj, Vivek J Bulbule, Francis C K Chiu, Jacques Chollet, Manickam Dhanasekaran, Christopher D Hein, Petros Papastogiannidis, Julia MorizziAbstract:Building on insights gained from the discovery of the antimalarial Ozonide arterolane (OZ277), we now describe the structure–activity relationship (SAR) of the antimalarial Ozonide artefenomel (OZ439). Primary and secondary amino Ozonides had higher metabolic stabilities than tertiary amino Ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino Ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino Ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino Ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino Ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these Ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity
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treatment of a chemoresistant neuroblastoma cell line with the antimalarial Ozonide oz513
BMC Cancer, 2016Co-Authors: Don W Coulter, Yuxiang Dong, Timothy R Mcguire, John G Sharp, Xiaofang Wang, Erin M Mcintyre, Shawn D Gray, Gracey R Alexander, Nagendra K Chatuverdi, Shantaram S JoshiAbstract:Background Evaluate the anti-tumor activity of Ozonide antimalarials using a chemoresistant neuroblastoma cell line, BE (2)-c.
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abstract b07 treatment of a chemoresistant human neuroblastoma cell line be 2c with experimental Ozonide antimalarials
Cancer Research, 2016Co-Authors: Don W Coulter, Yuxiang Dong, Timothy R Mcguire, John G Sharp, Xiaofang Wang, Erin M Mcintyre, Xiaoyu Chen, Jon VennerstromAbstract:Objective: To evaluate the anti-tumor activity of a class of experimental antimalarial drugs in an MYCN amplified chemoresistant neuroblastoma cell line (BE-2c) intended to model poor prognostic neuroblastoma. Methods: Etoposide cytotoxicity was studied at concentrations (250 ng/ml,500 ng/ml, 1 mcg/ml, 2 mcg/ml, and 3 mcg/ml) to confirm chemoresistance to a commonly used cytotoxic agent in the treatment of neuroblastoma. Concentrations chosen for the Ozonide antimalarials were those that have been achieved in-vivo when studied in a malarial model in rodents. Ozonide antimalarial drugs were tested in a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay which measures cell viability colorimetrically. A series of 13 Ozonide compounds were evaluated for activity using a concentration response scheme (0, 250 ng/ml, 500 ng/ml, 1 mcg/ml, 5 mcg/ml, and 10 mcg/ml) that allowed the generation of IC50 for each agent based on mean MTT absorption values from 10 replicates at each concentration. The most active Ozonide (OZ513) identified was then studied in a cell cycle flow cytometry analysis using propidium idodide with measurement of the A0 peak which estimates apoptosis. A neurosphere assay was also used which is considered enriched for “cancer stem cells” and is able to model movement of drug into a small avascular tumor was used to further evaluate the activity of OZ513. Spheres were counted and characterized after treatment and compared to non-treatment controls. Because it has been postulated that the anti-cancer mechanism of action of the Ozonide antimalarials is the modulation of cancer cell metabolism (autophagy, disruption of oxidative metabolism) the effect of OZ513 on mitochondrial oxidative metabolism and glycolysis was evaluated in BE-2c cells using Seahorse metabolic analysis. Results: Etoposide had no cytotoxic activity at any of the concentrations studied. OZ513 antimalarials were consistently active in BE-2c cell culture with the MTT assay generating IC50s on two separate experiments of 0.03 and 0.05 mcg/ml. The MTT results were confirmed using trypan blue staining to directly measure cell death. The Ao peak on PI flow cytometry increased after treatment with OZ513 indicating an increase in apoptosis. In addition, 5 mcg/ml of OZ513 increased G1, S, and G2 aneuploid fraction on propidium iodide cell cycle analysis. OZ513 disrupted BE-2c neurospheres confirming their activity in these multicellular tumorspheres. Metabolic studies demonstrated little effect on mitochondria based oxidative metabolism or glycolysis. Structure activity relationship suggests that the alcohol of the Ozonide structure is required for optimal activity. Conclusion: The antimalarial agent OZ513 has promising activity against the chemoresistant neuroblastoma cell-line BE-2c by increasing apoptosis by mechanisms that remain unclear, but increased cell cycle aneuploidy with treatment of cells with 5 mcg/ml of OZ513 indicates defects in mitosis and cytokinesis. Citation Format: Don W. Coulter, Timothy R. McGuire, John G. Sharp, Yuxiang Dong, Xiaofang Wang, Erin McIntyre, Xiaoyu Chen, Jon Vennerstrom. Treatment of a chemoresistant human neuroblastoma cell-line (BE-2c) with experimental Ozonide antimalarials. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B07.
Xiaofang Wang - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationship of antischistosomal Ozonide carboxylic acids
Journal of Medicinal Chemistry, 2020Co-Authors: Xiaofang Wang, Sriraghavan Kamaraj, Vivek J Bulbule, Francis C K Chiu, Cecile Haberli, David M Shackleford, Eileen Ryan, Alexander I Wallick, Yuxiang DongAbstract:Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal Ozonide carboxylic acids OZ418 (2) and OZ165 (3). Irrespective of lipophilicity, these Ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.
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Ozonide antimalarials alkylate heme in the malaria parasite plasmodium falciparum
ACS Infectious Diseases, 2019Co-Authors: Carlo Giannangelo, Jonathan L Vennerstrom, Xiaofang Wang, Susan A Charman, Dovile Anderson, Darren J CreekAbstract:The mechanism of action of Ozonide antimalarials involves activation by intraparasitic iron and the formation of highly reactive carbon-centered radicals that alkylate malaria parasite proteins. Given free intraparasitic heme is generally thought to be the iron source responsible for Ozonide activation and its likely close proximity to the activated drug, we investigated heme as a possible molecular target of the Ozonides. Using an extraction method optimized for solubilization of free heme, untargeted LC-MS analysis of Ozonide-treated parasites identified several regioisomers of Ozonide-alkylated heme, which resulted from covalent modification of the heme porphyrin ring by an Ozonide-derived carbon-centered radical. In addition to the intact alkylated heme adduct, putative Ozonide-alkylated heme degradation products were also detected. This study directly demonstrates Ozonide modification of heme within the malaria parasite Plasmodium falciparum, revealing that this process may be important for the biological activity of Ozonide antimalarials.
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structure activity relationship of the antimalarial Ozonide artefenomel oz439
Journal of Medicinal Chemistry, 2017Co-Authors: Yuxiang Dong, Xiaofang Wang, Sriraghavan Kamaraj, Vivek J Bulbule, Francis C K Chiu, Jacques Chollet, Manickam Dhanasekaran, Christopher D HeinAbstract:Building on insights gained from the discovery of the antimalarial Ozonide arterolane (OZ277), we now describe the structure–activity relationship (SAR) of the antimalarial Ozonide artefenomel (OZ439). Primary and secondary amino Ozonides had higher metabolic stabilities than tertiary amino Ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino Ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino Ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino Ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino Ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these Ozonides was most often associ...
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Structure–Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439)
2017Co-Authors: Yuxiang Dong, Xiaofang Wang, Sriraghavan Kamaraj, Vivek J Bulbule, Francis C K Chiu, Jacques Chollet, Manickam Dhanasekaran, Christopher D Hein, Petros Papastogiannidis, Julia MorizziAbstract:Building on insights gained from the discovery of the antimalarial Ozonide arterolane (OZ277), we now describe the structure–activity relationship (SAR) of the antimalarial Ozonide artefenomel (OZ439). Primary and secondary amino Ozonides had higher metabolic stabilities than tertiary amino Ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino Ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino Ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino Ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino Ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these Ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity
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treatment of a chemoresistant neuroblastoma cell line with the antimalarial Ozonide oz513
BMC Cancer, 2016Co-Authors: Don W Coulter, Yuxiang Dong, Timothy R Mcguire, John G Sharp, Xiaofang Wang, Erin M Mcintyre, Shawn D Gray, Gracey R Alexander, Nagendra K Chatuverdi, Shantaram S JoshiAbstract:Background Evaluate the anti-tumor activity of Ozonide antimalarials using a chemoresistant neuroblastoma cell line, BE (2)-c.
