The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase

Mori, Giorgia; Orena, Béatrice Silvia; Franch, Clara; Mitchenall, Lesley A.; Godbole, Adwait Anand; Rodrigues, Liliana; Aguilar-Pérez, Clara; Zemanová, Júlia; Huszár, Stanislav; Forbak, Martin; Lane, Thomas R.; Sabbah, Mohamad; Deboosère, Nathalie; Frita, Rosangela; Vandeputte, Alexandre; Hoffmann, Eik; Russo, Riccardo; Connell, Nancy; Veilleux, Courtney; Jha, Rajiv Kumar; Kumar, Pradeep; Freundlich, Joel S.; Brodin, Priscille; Aínsa, José A.; Nagaraja, Valakunja; Maxwell, Anthony; Mikušová, Katarı́na; Pasca, Maria Rosalia; Ekins, Sean

doi:10.1016/j.tube.2018.08.004

Cited by 13 publications

(15 citation statements)

References 82 publications

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“…For example, the LD 50 for pyronaridine in mice is reported as 1342 mg/kg, indicating relatively low toxicity (animals did not show behavioral abnormalities or neurotoxicity) as compared to chloroquine (LD 50 654 mg/kg) [17]. We are therefore currently evaluating the use of this compound against several pathogens [29, 31, 61]. It has been widely used in China for more than 30 years as a single agent against Plasmodium falciparum , the major causative parasite of malaria ( in vitro EC 50 = 13.5 nM [59]), and in multi-drug, artemisinin-based combination therapies (ACTs).…”

Section: Discussionmentioning

confidence: 99%

“…From our findings in this (Fig 4A) and a previous study, tilorone has 100% efficacy against maEBOV [37] which indicates immune modulation is at least partially responsible for tilorone’s efficacy. Pyronaridine demonstrates bioactivity against unrelated pathogens [29, 31, 61–63], pointing to a mechanism of action that may also involve a host effect (or common targets). Analysis of the current cytokine and chemokine data demonstrates pyronaridine does not illicit an immune response in unchallenged mice (not statistically different from both vehicle/naïve using Tukey’s HSD or Dunnett’s T3 test), but in maEBOV-challenged mice the response is equivalent to or increased from those treated with tilorone (Fig 6).…”

Section: Discussionmentioning

confidence: 99%

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Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection

et al. 2019

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Recent outbreaks of the Ebola virus (EBOV) have focused attention on the dire need for antivirals to treat these patients. We identified pyronaridine tetraphosphate as a potential candidate as it is an approved drug in the European Union which is currently used in combination with artesunate as a treatment for malaria (EC50 between 420 nM—1.14 μM against EBOV in HeLa cells). Range-finding studies in mice directed us to a single 75 mg/kg i.p. dose 1 hr after infection which resulted in 100% survival and statistically significantly reduced viremia at study day 3 from a lethal challenge with mouse-adapted EBOV (maEBOV). Further, an EBOV window study suggested we could dose pyronaridine 2 or 24 hrs post-exposure to result in similar efficacy. Analysis of cytokine and chemokine panels suggests that pyronaridine may act as an immunomodulator during an EBOV infection. Our studies with pyronaridine clearly demonstrate potential utility for its repurposing as an antiviral against EBOV and merits further study in larger animal models with the added benefit of already being used as a treatment against malaria.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection

et al. 2019

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“…Interestingly, it was reported that pyronaridine shows synergy with the potent anti-TB drug rifampicin, and that efflux does not play a major role in susceptibility to this drug. Further, it was proposed that interference with the metabolism of nucleic acids could be the main mechanism of M. tuberculosis inhibition [95].…”

Section: Pyronaridinementioning

confidence: 99%

Overcoming the Prokaryote/Eukaryote Barrier in Tuberculosis Treatment: A Prospect for the Repurposing and Use of Antiparasitic Drugs

2021

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Antimicrobial resistance, the so-called silent pandemic, is pushing industry and academia to find novel antimicrobial agents with new mechanisms of action in order to be active against susceptible and drug-resistant microorganisms. In the case of tuberculosis, the need of novel anti-tuberculosis drugs is specially challenging because of the intricate biology of its causative agent, Mycobacterium tuberculosis. The repurposing of medicines has arisen in recent years as a fast, low-cost, and efficient strategy to identify novel biomedical applications for already approved drugs. This review is focused on anti-parasitic drugs that have additionally demonstrated certain levels of anti-tuberculosis activity; along with this, natural products with a dual activity against parasites and against M. tuberculosis are discussed. A few clinical trials have tested antiparasitic drugs in tuberculosis patients, and have revealed effective dose and toxicity issues, which is consistent with the natural differences between tuberculosis and parasitic infections. However, through medicinal chemistry approaches, derivatives of drugs with anti-parasitic activity have become successful drugs for use in tuberculosis therapy. In summary, even when the repurposing of anti-parasitic drugs for tuberculosis treatment does not seem to be an easy job, it deserves attention as a potential contributor to fuel the anti-tuberculosis drug pipeline.

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“…PYR promoted inhibition of RNA polymerase activity by rifampicin. [84] Very recently, PYR was identified as a promising drug candidate to treat cystic echinococcosis, which are serious infectious diseases, affecting both Humans and animals, caused by the pathogen Echinococcus granulosus, without efficacious remedy. Interestingly, an oral treatment with PYR significantly reduced the parasitic burden in infected mice.…”

Section: Activities Of Pyronaridine Against Other Parasitesmentioning

confidence: 99%

Pyronaridine: An update of its pharmacological activities and mechanisms of action

Bailly

2020

Biopolymers

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Pyronaridine (PYR) is an erythrocytic schizonticide with a potent antimalarial activity against multidrug-resistant Plasmodium. The drug is used in combination with artesunate for the treatment of uncomplicated P. falciparum malaria, in adults and children. The present review briefly retraces the discovery of PYR and recent antimalarial studies which has led to the approval of PYR/artesunate combination (Pyramax) by the European Medicines Agency to treat uncomplicated malaria worldwide. PYR Pyronaridine (PYR, Figure 1), initially known as "antimalaria drug 7351", is a benzo-naphthyridine derivative originally synthesized in 1979 [1] and developed in China from the early 1980s. [2][3][4] Rapidly, experimental studies demonstrated that this compound was more active than chloroquine against different isolates of Plasmodium falciparum, the malaria pathogen.

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The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase

Cited by 13 publications

References 82 publications

Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection

Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection

Overcoming the Prokaryote/Eukaryote Barrier in Tuberculosis Treatment: A Prospect for the Repurposing and Use of Antiparasitic Drugs

Pyronaridine: An update of its pharmacological activities and mechanisms of action

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