Developing constrained peptides as UBL-pathway antimalarials

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Malaria is a major tropical and sub-tropical disease which was estimated by the World Health Organisation (WHO) to be responsible for the deaths of around 430,000 - 450,000 people annually. It is also estimated that there are around 215 million cases of malaria annually spanning over 90 countries. The disease is caused by the unicellular eukaryotic parasite Plasmodium, of which Plasmodium falciparum is the most deadly and prominent of the species to infect humans. Plasmodium has a digenetic life cycle which is split between a mammalian and a anopheles mosquito host. There are a range of medications available to treat malaria infected individuals but increasing drug resistance of Plasmodium species to these current treatments is of global concern. The aim of this project will be to investigate whether constrained peptides can be used as a new form of anti-malarial treatment.The target of the peptides is PfUCHL3, an essential and well characterised deubiquitinating enzyme (DUB) of P. falciparum. DUBs are involved in the removal of ubiquitin from proteins and can alter the targeted proteins fate and function within the cell. PfUCHL3 is well suited to in-vitro studies because it can be purified to high concentrations and purity, furthermore crystal structures of PfUCHL3 alone and in complex with a ubiquitin probe (Ub-VME) have been solved. Inhibiting the ubiquitin-PfUCHL3 protein-protein interaction is expected to be cell lethal and using constrained peptides to do so has many advantages.Constraining a peptide helps lock it into its bioactive, binding-competent conformation. It also helps rigidify its structure, make it more protease resistant and helps increase its binding affinity and cell permeability. Peptides in this project will be constrained by either cyclisation, peptide stapling or by using scaffold proteins. The main aim of this project is to generate and biophysically characterise a library of constrained peptides which can bind to and potentially inhibit PfUCHL3.