Antimalarial activity of primaquine operates via a two-step biochemical relay

Camarda, Grazia; Jirawatcharadech, Piyaporn; Priestley, Richard S.; Saif, Ahmed; March, Sandra; Wong, Michael H. L.; Leung, Suet C.; Miller, Arnold; Baker, David A.; Alano, Pietro; Paine, Mark J. I.; Bhatia, Sangeeta N.; O’Neill, Paul M.; Ward, Stephen A.; Biagini, Giancarlo A.

doi:10.1038/s41467-019-11239-0

Cited by 117 publications

(115 citation statements)

References 36 publications

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“…The resulting amino-phenol undergoes facile oxidation to the quinone-imine by oxygen resulting in generation of ROS. In the presence of the flavoenzyme cytochrome P450 NADPH:oxidoreductase, the quinone-imine is reduced to the amino-phenol, and thus redox cycling ensues (Camarda et al, 2019). It is the ROS that exert cytotoxicity toward gametocytes; this redox cycling precisely mirrors the process as described above for methylene blue.…”

Section: Discussionmentioning

confidence: 86%

Optimal 10-Aminoartemisinins With Potent Transmission-Blocking Capabilities for New Artemisinin Combination Therapies–Activities Against Blood Stage P. falciparum Including PfKI3 C580Y Mutants and Liver Stage P. berghei Parasites

et al. 2020

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We have demonstrated previously that amino-artemisinins including artemiside and artemisone in which an amino group replaces the oxygen-bearing substituents attached to C-10 of the current clinical artemisinin derivatives dihydroartemisinin (DHA), artemether and artesunate, display potent activities in vitro against the asexual blood stages of Plasmodium falciparum (Pf). In particular, the compounds are active against late blood stage Pf gametocytes, and are strongly synergistic in combination with the redox active drug methylene blue. In order to fortify the eventual selection of optimum amino-artemisinins for development into new triple combination therapies also active against artemisinin-resistant Pf mutants, we have prepared new amino-artemisinins based on the easily accessible and inexpensive DHA-piperazine. The latter was converted into alkyl-and aryl sulfonamides, ureas and amides. These derivatives were screened together with the comparator drugs DHA and the hitherto most active amino-artemisinins artemiside and artemisone against asexual and sexual blood stages of Pf and liver stage P. berghei (Pb) sporozoites. Several of the new amino-artemisinins bearing aryl-urea and-amide groups are potently active against both asexual, and late blood stage gametocytes (IC 50 0.4-1.0 nM). Although the activities are superior to those of artemiside (IC 50 1.5 nM) and artemisone (IC 50 42.4 nM), the latter are more active against the liver stage Pb sporozoites (IC 50 artemisone 28 nM). In addition, early results indicate these compounds tend not to display reduced susceptibility against parasites bearing the Pf Kelch 13 propeller domain C580Y mutation characteristic of Wong et al. Transmission-Blocking Amino-Artemisinins for New ACTs artemisinin-resistant Pf. Thus, the advent of the amino-artemisinins including artemiside and artemisone will enable the development of new combination therapies that by virtue of the amino-artemisinin component itself will possess intrinsic transmission-blocking capabilities and may be effective against artemisinin resistant falciparum malaria.

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Section: Discussionmentioning

confidence: 86%

Optimal 10-Aminoartemisinins With Potent Transmission-Blocking Capabilities for New Artemisinin Combination Therapies–Activities Against Blood Stage P. falciparum Including PfKI3 C580Y Mutants and Liver Stage P. berghei Parasites

et al. 2020

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“…Specifically, 4AQs kill malaria parasites with the same mode of action as has been proposed for their anti-coronavirus effects, by increasing intravacuolar pH [22,24]. While mechanisms of action of 8AQs are poorly defined, recent studies have suggested malaria parasites are killed site-specifically by hydrogen peroxide accumulation generated by a two-step biochemical relay involving monooxygenases and cytochrome P450:NADPH oxidoreductase [6]. Also, tafenoquine is active against the lung pathogen Pneumocystis in vitro and in vivo at pharmacologically relevant concentrations and doses [4,16].…”

Section: Manuscript Textmentioning

confidence: 97%

“…Tafenoquine [TQ], an FDA-approved 8-aminoquinoline [8AQ] antimalarial, can be administered orally, weekly, for up to six months, and is differentiated relative to the 4-aminoquinolines [4AQs] hydroxychloroquine (HCQ) and chloroquine (CQ) in that it does not prolong QTc interval and acts more broadly against a variety of malaria life cycle stages via different mechanisms of action [1, 6,10]. Specifically, 4AQs kill malaria parasites with the same mode of action as has been proposed for their anti-coronavirus effects, by increasing intravacuolar pH [22,24].…”

Section: Manuscript Textmentioning

confidence: 99%

Tafenoquine inhibits replication of SARS-Cov-2 at pharmacologically relevant concentrations in vitro

Dow¹,

Luttick²,

Fenner³

et al. 2020

Preprint

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Tafenoquine [TQ] exhibited EC50/90s of approximately 2.6/5.1 microM against SARS-CoV-2 in VERO E6 cells and was 4-fold more potent than hydroxychloroquine [HCQ]. Time-of-addition experiments were consistent with a different mechanism for TQ v HCQ. Physiologically based pharmacokinetic (PBPK) modeling suggested that lung unbound concentrations of TQ in COVID-19 patients may exceed the EC90 for at least 8 weeks after administration. The therapeutic potential for TQ in management of COVID-19 should be further evaluated.

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“…It should be pointed out that there are many FDA approved drugs for which the mechanism is unknown. It is only in recent years that we have started to unravel the mechanism of action of such drugs that were approved decades ago (29, 30). The focus of our current efforts is on assessing pyronaridine and other clinical stage compounds as possible treatments for EBOV.…”

Section: Introductionmentioning

confidence: 99%

Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig

Lane

Massey²,

Comer³

et al. 2020

Preprint

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31The recent outbreaks of the Ebola virus (EBOV) in Africa have brought global visibility to 32 the shortage of available therapeutic options to treat patients infected with this or closely 33 related viruses. We have recently computationally identified three molecules which have 34 all demonstrated statistically significant efficacy in the mouse model of infection with 35 mouse adapted Ebola virus (ma-EBOV). One of these molecules is the antimalarial 36 pyronaridine tetraphosphate (IC 50 range of 0.82-1.30 µM against three strains of EBOV 37 and IC 50 range of 1.01-2.72 µM against two strains of Marburg virus (MARV)) which is 38 an approved drug in the European Union and used in combination with artesunate. To 39 date, no small molecule drugs have shown statistically significant efficacy in the guinea 40 pig model of EBOV infection. Pharmacokinetics and range-finding studies in guinea pigs 41 directed us to a single 300mg/kg or 600mg/kg oral dose of pyronaridine 1hr after 42 infection. Pyronaridine resulted in statistically significant survival of 40% at 300mg/kg 43 and protected from a lethal challenge with EBOV. In comparison, oral favipiravir (300 44 mg/kg dosed once a day) had 43.5 % survival. The in vitro metabolism and metabolite 45 identification of pyronaridine and another of our EBOV active molecules, tilorone, which 46 suggests significant species differences which may account for the efficacy or lack 47 thereof, respectively in guinea pig. In summary, our studies with pyronaridine 48 demonstrates its utility for repurposing as an antiviral against EBOV and MARV, 49 providing justification for future testing in non-human primates. 50 51 52 4 Importance 53There is currently no antiviral small molecule drug approved for treating Ebola Virus 54 infection. We have previously used machine learning models to identify new uses for 55 approved drugs and demonstrated their activity against the Ebola virus in vitro and in 56 vivo. We now describe the pharmacokinetic properties of the antimalarial pyronaridine in 57 the guinea pig. In addition, we show that this drug is effective against multiple strains of 58 EBOV and MARV in vitro and in the guinea pig model of Ebola virus infection. These 59 combined efforts indicate the need to further test this molecule in larger animal efficacy 60 studies prior to clinical use in humans. These findings also may be useful for 61 repurposing this drug for use against other viruses in future. 62 63

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Antimalarial activity of primaquine operates via a two-step biochemical relay

Cited by 117 publications

References 36 publications

Optimal 10-Aminoartemisinins With Potent Transmission-Blocking Capabilities for New Artemisinin Combination Therapies–Activities Against Blood Stage P. falciparum Including PfKI3 C580Y Mutants and Liver Stage P. berghei Parasites

Optimal 10-Aminoartemisinins With Potent Transmission-Blocking Capabilities for New Artemisinin Combination Therapies–Activities Against Blood Stage P. falciparum Including PfKI3 C580Y Mutants and Liver Stage P. berghei Parasites

Tafenoquine inhibits replication of SARS-Cov-2 at pharmacologically relevant concentrations in vitro

Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig

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