Production of Trypanosome cruzi Trans-sialidase inhibitory antibodies.

URRUTIA M, RATIER L, PARIS G, ZAREBSKI L, FRASCH A, GOLDBAUM F.

Angra dos Reis, Brasil.

Conferencia; 1st. Latin American Protein Society Meeting.; 2004

In recent years, great effort has been undertaken to search for molecules which interfere with the Trypanosoma cruzi infection associated with Chagas disease. Trypanosomatids are unable to synthesize sialic acid de novo, they have a trans-sialidase (TS) which catalyses the transfer of sialic acid residues from hosts to parasite glycoconjugates. This reaction appears to be critical for T. Cruzi survival and cell invasion capability.  Trypanosoma cruzi trans-sialidase (TcTS) constitutes a key molecule in both the establishment of the infection and in the development of pathologic abnormalities related with Chagas disease. Poor effect of known sialidase (S) inhibitors can be attributed to modified binding profile and unfavourable steric clashes.    To increase the chance of producing antibodies with inhibitory capacity we took advantage of the fact that camelids produce, additionally to conventional antibodies, unusual immunoglobulins devoid of light chains. Their binding site is formed solely by one variable region (VHH) as it is shown in Fig. 1. The binding strategies of these antibodies are very particular, their CDR3 region form long extensions that can extent into cavities on antigens, e.g. the active site crevice of enzymes, as it can be observed in Fig. 2. Thus, VHHs are a suitable fragment for the development of enzyme inhibitors.