- This event has passed.
Prof Anthony Moore: “The alternative oxidase: a novel therapeutic target for the treatment of trypanosomiasis, cryptosporidiosis and candidiasis”
27th May 2015 @ 3:00 pm - 4:00 pmFree
The alternative oxidase: a novel therapeutic target for the treatment of trypanosomiasis, cryptosporidiosis and candidiasis.
Wed, 27 May, 2015
Lecture Theatre, Level 7
The alternative oxidase (AOX) is a ubiquinol oxidoreductase that catalyses the four electron reduction of oxygen to water. It is ubiquitous amongst plants, some fungi and protists. Importantly it is widespread amongst human parasites such as Trypanosoma brucei (the causative agent of African Sleeping Sickness), intestinal parasites such as Cryptosporidium parvum and Blastocystis hominis and opportunistic human pathogens such as Candida albicans. It should be noted that immunocompromised individuals are particularly susceptible to these opportunistic human diseases, and new drugs that are well tolerated and have clearly defined biochemical targets are therefore urgently required. Since AOX is absent from the human host and is essential for the life-cycle of the trypanosomal parasite within the blood-stream there is growing support for this protein to be considered as a novel therapeutic target for the treatment of trypanosomiasis and other diseases in which AOX plays a key metabolic role. Treatment of mice infected with trypanosomes by ascofuranone (AF) rapidly clears the parasite from the bloodstream without any adverse effects upon the animal. Furthermore the chemotherapeutic efficacy of AF in vivo has been confirmed. Our recent crystal structures demonstrated that AOX is a homo-dimer with each monomer being comprised of 6 long alpha-helices, 4 of which form a 4 helix bundle which acts as a scaffold to bind the two iron atoms. The iron atoms within the active-site under oxidised conditions are co-ordinated by 4 glutamate residues but no histidine residues which is an unusual co-ordination for a diiron protein. We have also obtained high resolution crystal structures of AOX in the presence of a number of AF-derivatives thereby defining the nature and location of the inhibitor-binding pocket, the residues which are hydrogen-bonded to the inhibitor and provided substantial information on the binding of ubiquinol within the active-site. Such information is important for the future rational design of anti-parasitic drugs which specifically targeted at the AOX and may prove critical for the treatment of diseases such as trypanosomiasis, cryptosporidiosis and candidiasis.