Professor Alan Fairlamb

Biochemical Drug Targets in Parasites

Better, safer and affordable drugs are needed for neglected tropical parasitic diseases. My research interests cover the early aspects of the drug discovery process, including discovery of novel drug targets, their mechanistic and structural characterisation and their validation using genetic and chemical approaches. My studies on the modes of drug action and the mechanisms by which parasites acquire resistance to drugs such as the arsenical, melarsoprol, resulted in the discovery of trypanothione, a metabolite unique to trypanosomatid parasites responsible for human African trypanosomiasis, Chagas' disease and leishmaniasis. Trypanothione and its ancillary enzymes are attractive drug targets, because they play a central role in thiol-redox homeostasis, in defence against chemical and oxidative stress, in resistance to antimonial drugs and in the metabolism of deoxyribonucleotides and methylglyoxal. In particular, the unique biosynthetic enzyme, trypanothione synthetase, has been shown to be an essential and druggable target. My research team has also established that certain enzymes of folate, pterin and pyridoxal metabolism are attractive drug targets in trypanosomes. Currently we are investigating the modes of action of potential new therapies for trypanosomiasis and leishmaniasis, including fexinidazole and PA-824.