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Two orthogonal peptide combinatorial libraries were screened to discover inhibitors of Tc80 protease, a novel target from Trypanosoma cruzi involved in host cell invasion. These libraries were composed of 15,625 structurally diversified tripeptides, partitioned in 125 mixtures. The screening led to a low micromolar inhibitor which was actually an HF cleavage by-product H-Ipe-D-Tic-D-Glu(S-paratolyl)-OH. IC50 values of several analogous molecules of this hit were determined and are discussed. For the best compounds, conformational analysis revealed a high degree of similarity in shape with a potent prolylendopeptidase inhibitor, SUAM-1221.

Identification of Inhibitors of an 80kDa Protease from Trypanosoma cruzi through the Screening of a Combinatorial Peptide Library.