Identification of inhibitors of an 80 kDa protease from Trypanosoma cruzi through the screening of a combinatorial peptide library

Two orthogonal peptide combinatorial libraries were screened to discover in hibitors of Tc80 protease, a novel target from Trypanosoma cruzi involved i n host cell invasion. These libraries were composed of 15625 structurally d iversified tripeptides, partitioned in 125 mixtures, The screening led to a low micromolar inhibitor which was actually an HF cleavage by-product H-Ip e-D-Tic-D-Glu(S-paratolyl)-OH. IC50 values of several analogous molecules o f this hit were determined and are discussed. For the best compounds, confo rmational analysis revealed a high degree of similarity in shape with a pot ent prolylendopeptidase inhibitor, SUAM-1221.