Joint project
HR24 - La Caixa Health Project: Redox metabolism as an Achilles’ heel in Malaria drug discovery
Funder: Fundación Bancaria Caixa d’Estalvis i Pensions de Barcelona
Period: 2024-2027
Abstract:
Plasmodium falciparum is particularly susceptible to oxidative and nitrosative stress. The project aims to identify inhibitors specific to redox enzymes in malarial parasites leading to parasite death.
Detailed description:
Malaria caused by P. falciparum kills over 400,000 people annually. The parasite’s development of resistance to antimalarial treatment led to the prioritization of research on novel drug targets. The parasite undergoes a complex life cycle and must rapidly adapt and respond to changing cellular conditions and stress, including that generated by processes essential to parasite survival. In contrast to other systems, P. falciparum lacks the main redox regulators, namely the enzymes catalase and glutathione peroxidase. So, a reduced system of redox mediators has evolved based on the thioredoxin and glutathione systems. At the heart of these systems lie the enzymes thioredoxin reductase (TrxR) and glutathione reductase (GR). Previous studies have highlighted significant differences in these enzymes’ structural and biochemical characteristics compared to human homologs and verified them as potential
targets for drug development.
GReat proposes an interdisciplinary approach using protein-directed dynamic combinatorial chemistry (PD-DCC) assisted by in silico virtual screening and binding affinity calculations to discover specific inhibitors of Plasmodium enzymes. In PD-DCC, the protein synthesises the best ligand in situ. To selectively target the parasite enzymes, computational studies will lead the design of the building blocks for PD-DCC, focusing on the structural differences between both enzymes. Identified hits will be used in in vitro assays on purified enzymes from the parasite and human host. Their binding affinity and kinetics to the target protein are analysed by surface plasmon resonance. Specifically, candidates will be tested in in vitro parasite culture for their ability to block parasite proliferation. Furthermore, the mode of action will then be studied using parasites expressing genetically encoded redox sensors. GReat will bring highly selective inhibitors of the parasite life cycle without interfering with the normal functioning of
human cells.
Malaria caused by P. falciparum kills over 400,000 people annually. The parasite’s development of resistance to antimalarial treatment led to the prioritization of research on novel drug targets. The parasite undergoes a complex life cycle and must rapidly adapt and respond to changing cellular conditions and stress, including that generated by processes essential to parasite survival. In contrast to other systems, P. falciparum lacks the main redox regulators, namely the enzymes catalase and glutathione peroxidase. So, a reduced system of redox mediators has evolved based on the thioredoxin and glutathione systems. At the heart of these systems lie the enzymes thioredoxin reductase (TrxR) and glutathione reductase (GR). Previous studies have highlighted significant differences in these enzymes’ structural and biochemical characteristics compared to human homologs and verified them as potential
targets for drug development.
GReat proposes an interdisciplinary approach using protein-directed dynamic combinatorial chemistry (PD-DCC) assisted by in silico virtual screening and binding affinity calculations to discover specific inhibitors of Plasmodium enzymes. In PD-DCC, the protein synthesises the best ligand in situ. To selectively target the parasite enzymes, computational studies will lead the design of the building blocks for PD-DCC, focusing on the structural differences between both enzymes. Identified hits will be used in in vitro assays on purified enzymes from the parasite and human host. Their binding affinity and kinetics to the target protein are analysed by surface plasmon resonance. Specifically, candidates will be tested in in vitro parasite culture for their ability to block parasite proliferation. Furthermore, the mode of action will then be studied using parasites expressing genetically encoded redox sensors. GReat will bring highly selective inhibitors of the parasite life cycle without interfering with the normal functioning of
human cells.
Cooperation partners with funding
- Center for Cooperative Research in Biosciences
