Laboratory of Pathogens and Host Immunity

Development of new compounds and evaluation of their antimalarial potential

Theme leader: Rachel Cerdan


Project 1: Development of purine analogues as potent antimalarial compounds.

PIs: Rachel Cerdan and Sharon Wein

We have identified a novel series of AcycloNucleoside Phosphonates (ANPs) with significant antimalarial activity in vitro against asexual blood stages and efficacy in vivo (P. vinckei- and P. berghei-infected mice). The lead compound shows an antimalarial activity in the nanomolar range with a very high selectivity index. ANPs are structurally unrelated to existing drugs and they have an original mode of action.

Our objectives are:

  • to optimize the lead compound of this class and to design an orally administrable molecule that is suitable to be developed in the preclinical phase.
  • to assess the inhibitory potential of the compound on the different stages of the life cycle of the Plasmodium parasite.
  • to decipher its mode of action by identifying and validating its therapeutic target.

Project 2: Evaluation of a new principle of antimalarial strategy through the chemical activation of the host cell specific mechano-sensitive ion channel Piezo1.

PI: Kai Wenglenik

Piezo channels are mechanosensitive cation channels of higher eukaryotic organisms that are absent from Plasmodium species or other apicomplexan parasites. Red blood cells (RBCs) express only the Piezo1 channel. A link between Piezo1 function and malaria infection has first been shown using a mouse model. The protective phenotype has been linked to the hydration status of the RBCs. Most interestingly, this study also identified a new polymorphism in human Piezo1 that is very abundant in healthy people of African origin (about 30% of carriers). This polymorphism confers a reduction in RBC infection rates by P. falciparum in in vitro cultures. Currently very few compounds have been described to interfere with Piezo1 function, the most widely used being the Piezo1 activator Yoda1.

The aims of our project are the following:

  • Characterisation of the protective effect of Piezo1 activation through chemical stimulation on falciparum infection.
  • Identification and selection of new Piezo1 activators with potent antimalarial activity.
  • Evaluation whether the chemical activation of Piezo1 of the human RBC could serve as a new principle of antimalarial strategy since we are targeting a host cell protein and not the parasite itself.