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Projeto de investigação
Novel Cel-based platform for drug screening targeting plasmodium hepatic infection
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Pre-erythrocytic activity of M5717 in monotherapy and combination in preclinical Plasmodium infection models
Publication . Fontinha, Diana; Arez, Francisca; Gal, Isabella Ramella; Nogueira, Gonçalo; Moita, Diana; Baeurle, Tobias Hyun Ho; Brito, Catarina; Spangenberg, Thomas; Alves, Paula M.; Prudêncio, Miguel
Combination therapies have emerged to mitigate Plasmodium drug resistance, which has hampered the fight against malaria. M5717 is a potent multistage antiplasmodial drug under clinical development, which inhibits parasite protein synthesis. The combination of M5717 with pyronaridine, an inhibitor of hemozoin formation, displays potent activity against blood stage Plasmodium infection. However, the impact of this therapy on liver infection by Plasmodium remains unknown. Here, we employed a recently described 3D culture-based hepatic infection platform to evaluate the activity of the M5717-pyronaridine combination against hepatic infection by P. berghei. This effect was further confirmed in vivo by employing the C57BL/6J rodent Plasmodium infection model. Collectively, our data demonstrate that pyronaridine potentiates the activity of M5717 against P. berghei hepatic development. These preclinical results contribute to the validation of pyronaridine as a suitable partner drug for M5717, supporting the clinical evaluation of this novel antiplasmodial combination therapy.
Translation of liver stage activity of M5717, a Plasmodium elongation factor 2 inhibitor: from bench to bedside
Publication . Khandelwal, Akash; Arez, Francisca; Alves, Paula M.; Badolo, Lassina; Brito, Catarina; Fischli, Christoph; Fontinha, Diana; Oeuvray, Claude; Prudêncio, Miguel; Rottmann, Matthias; Wilkins, Justin; Yalkinoglu, Özkan; Bagchus, Wilhelmina M.; Spangenberg, Thomas
Background: Targeting the asymptomatic liver stage of Plasmodium infection through chemoprevention could become a key intervention to reduce malaria-associated incidence and mortality.
Methods: M5717, a Plasmodium elongation factor 2 inhibitor, was assessed in vitro and in vivo with readily accessible Plasmodium berghei parasites. In an animal refinement, reduction, replacement approach, the in vitro IC99 value was used to feed a Population Pharmacokinetics modelling and simulation approach to determine meaningful effective doses for a subsequent Plasmodium sporozoite-induced volunteer infection study.
Results: Doses of 100 and 200 mg would provide exposures exceeding IC99 in 96 and 100% of the simulated population, respectively.
Conclusions: This approach has the potential to accelerate the search for new anti-malarials, to reduce the number of healthy volunteers needed in a clinical study and decrease and refine the animal use in the preclinical phase.
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Fundação para a Ciência e a Tecnologia
Programa de financiamento
OE
Número da atribuição
PD/BD/128371/2017