Structure-based drug discovery using trehalose-6-phosphate phosphatase, an infectious disease target

Megan Cross, University, My, Andreas Hofmann
Over 400 million people are currently affected by parasitic worm infections. While seldom fatal, the long-term consequences of helminthiases are significant and global burden is estimated at 22 million disability adjusted life years per annum. Amid growing concerns of zoonosis, treatment resistance and geographical expansion, there has been a call for the development of novel anti-parasitic strategies. To minimise potential treatment side effects, common approaches target proteins that are
more » ... tial for parasite survival but absent from the host genome. One such target is the essential enzyme trehalose-6-phosphate phosphatase (TPP), the final enzyme in the trehalose biosynthesis pathway. TPP is essential for roundworm survival, a validated target for the treatment of tuberculosis and also shows promise as a vaccine against the nematode Brugia malayi, the causative agent of lymphatic filariasis. This work focuses on the TPP enzymes of the parasitic nematodes Toxocara canis and Ancylostoma ceylanicum as the centre of a target-based approach to identify novel TPP inhibitors with potential as early drug discovery leads. Structure-based sequence analysis of the TPP enzymes of a range of pathogens supported the proposal of three topological groups with structural differences and revealed species-specific variation in what is otherwise considered a highly conserved enzyme family. To account for interspecies variation during downstream drug discovery work, the TPPs of Mycobacterium tuberculosis, Stenotrophomonas maltophilia and Pseudomonas aeruginosa were added to the study, forming a panel of nematode and bacterial TPPs. Enzymatic characterisation of these enzymes revealed that they are kinetically suited to their physiological function and largely employ superstoichiometric burst kinetics, which suggests a role for conformational change during catalysis. To identify novel scaffolds for TPP inhibition, 5,452 compounds were screened as potential TPP ligands. Of these, 222 compounds (4% selection rate) were selected and t [...]
doi:10.25904/1912/1200 fatcat:qc3adkch6jggffxj4xzbceyr3e