Development of peptoid-based antimalarial histone deacetylase inhibitors with multi-stage activity

• Applicants: Professor Dr. Finn Kristian Hansen; Dr. Jana Held
• Subject Area: Pharmacy
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 285846829

Malaria remains a life-threatening disease in tropical and subtropical regions of the world. Most current antimalarials are only active against the asexual blood stages of the parasite, which are responsible for the clinical symptoms of malaria. However, recent drug discovery efforts have moved towards supporting the aim of eradicating malaria, and seek to additionally target exo-eryothrocytic liver stage parasites and/or gametocytes. As part of this project, we intend to develop novel antiplasmodial histone deacetylase inhibitors (HDACi) with activity against multiple malaria parasite life cycle stages.Histone deacetylases (HDACs) are important enzymes for the epigenetic modulation of gene expression by altering chromatin structures. So far, five HDAC encoding genes have been identified in the Plasmodium falciparum genome. Phenotypic screening campaigns led to the discovery of several HDACi with potent antimalarial activity. Unfortunately, unselective HDACi and class I selective HDACi exhibited high toxicity to human cells resulting in a low to moderate parasite selectivity. Thus, we hypothesized that class II selective human HDACi might be a better starting point for the development of parasite-selective antimalarial HDACi. During the first phase of this project, we successfully demonstrated the applicability of this approach. Starting from a series of peptoid-based human HDAC6 inhibitors, we identified a series of HDACi with potent and selective activity against drug sensitive and drug resistant asexual blood stage parasites, and submicromolar activity against liver stage parasites. In the second phase of the project, we are planning to utilize the established structure-activity and structure-toxicity relationships to further optimize this series of compounds. The zinc-binding group, the linker region, and the lipophilic capping group, which represent the three main structural elements of HDACi, will be independently varied and the resulting compounds will be tested for their antiplasmodial properties. The emerging resistance of P. falciparum to artemisinin-based combination therapies highlights the urgent need for new concepts to tackle drug resistance. To this end, we will investigate whether artemisinin resistance can be addressed using combinations of artemisinin derivatives and HDACi as well as dihydroartemisinin-HDACi hybrid compounds in artemisinin-resistant laboratory P. falciparum strains. The most promising HDACi and dihydroartemisinin-HDACi hybrids will be studied ex vivo in P. falciparum isolates and in vivo using P. berghei infected mice.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Professorin Elizabeth Winzeler, Ph.D.