Investigating mammalian tyrosine phosphatase inhibitors as potential 'piggyback' leads to target Trypanosoma brucei transmission.
African trypanosomiasis is a neglected tropical disease affecting humans and animals across 36 sub-Saharan African countries. We have investigated the potential to exploit a 'piggyback' approach to inhibit Trypanosoma brucei transmission by targeting the key developmental regulator of transmission, T. brucei protein tyrosine phosphatase 1. This strategy took advantage of the extensive investment in inhibitors for human protein tyrosine phosphatase 1B, a key target for pharmaceutical companies for the treatment of obesity and diabetes. Structural predictions for human and trypanosome tyrosine phosphatases revealed the overall conservation of important functional motifs, validating the potential for exploiting cross specific compounds. Thereafter, nineteen inhibitors were evaluated; seventeen from a protein tyrosine phosphatase 1B-targeted inhibitor library and two from literature analysis - oleanolic acid and suramin, the latter of which is a front line drug against African trypanosomiasis. The compounds tested displayed similar inhibitory activities against the human and trypanosome enzymes, mostly behaving as noncompetitive inhibitors. However, their activity against T. brucei in culture was low, necessitating further chemical modification to improve their efficacy and specificity. Nonetheless, the results validate the potential to explore a 'piggyback' strategy targeting T. brucei protein tyrosine phosphatase 1 through exploiting the large pharmacological investment in therapies for obesity targeting protein tyrosine phosphatase 1B.
Centre for Immunity, Infection and Evolution, School of Biological Sciences, Institute of Immunology and Infection Research, University of Edinburgh, King's Building, West Mains Road, Edinburgh EH9 3JT, UK.
Irene
I
Ruberto
Balazs
B
Szoor
Rachel
R
Clark
Keith R
KR
Matthews
D000818:Animals; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013498:Suramin / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000517:prevention & control / Q000635:transmission
D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D013498:Suramin; D017027:Protein Tyrosine Phosphatases