Pre-erythrocytic activity of M5717 in monotherapy and combination in preclinical Plasmodium infection models

Copyright © 2022 The Authors. Published by American Chemical SocietyCombination 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.This work was funded by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945). M.P. is a recipient of a “Concurso de Estímulo ao Emprego Científico” Principal Investigator award of Fundação para a Ciência e Tecnologia, Portugal (FCT), with ref. N. CEECIND/03539/2017. D.F. is funded by FCT project CRCNA/BRB/0281/2019. F.A. is recipient of a PhD fellowship PD/BD/128371/2017, funded by FCT.info:eu-repo/semantics/publishedVersio