Structural and pharmacological study of Trypanosoma cruzi trans-sialidase

Abstract

Chagas disease affects millions of people in Latin America and is now spreading to the whole world. Causing by the infection of Trypanosoma cruzi (T. cruzi), Chagas disease can be fatal, patients suffering from severe intestinal and cardiac disorders. The development of diagnosis and therapeutic drugs against Chagas disease is slow so far due to limited investment. T. cruzi trans sialidase (TcTS) is a surface-anchored glycoside transferase which plays a critical role in host cell invasion and immune evasion. Its uniqueness and role in parasite survival and pathogenicity indicates the importance of TcTS as a potential target for therapeutic drug development. However, no sufficiently strong inhibitors of TcTS have been described. Based on the structure of sialyl-lactose, a natural substrate of TcTS, we have designed a new type of inhibitor, α aminophosphonate, which inhibits TcTS effectively and selectively when compared to inhibition of bacterial sialidases/neuraminidases.

Interestingly, although the compound was designed to interact with the catalytic site, it showed noncompetitive inhibition. Crystal structures suggest an allosteric binding site and the interaction between TcTS and α-aminophosphonate causes only minor conformational changes. Binding of α-aminophosphonate may inhibit TcTS activity by inducing these conformational changes and increasing the structural stability of catalytic site This results in stable binding of lactose, which is also shown through thermodynamics. Additionally, anthraquinone derivatives, whether an individual compound or as a part of an α-aminophosphonate, inhibit TcTS non-competitively, but these are shown to bind to the lactose-binding site, part of the catalytic pocket, also giving new insight into the inhibition and catalytic mechanisms of TcTS.

In conclusion, α-aminophosphonate may be a potential drug candidate for Chagas disease. The crystal structure of TcTS in complex with α-aminophosphonate compound is the first report of the TcTS allosteric binding site, which may be crucial for better understanding of the mechanisms and substrate recognition of this vital enzyme and for rational drug design.

Date of Award	1 Oct 2017
Original language	English
Awarding Institution	University of Bath
Supervisor	Susan Crennell (Supervisor), Jean Van Den Elsen (Supervisor) & Andrew Watts (Supervisor)