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

• Published in: Chemical & pharmaceutical bulletin Vol. 47; no. 2; pp. 194 - 198
• Main Authors: VENDEVILLE, Sandrine, BUISINE, Eric, WILLIARD, Xavier, SCHREVEL, Joseph, GRELLIER, Philippe, SANTANA, Jaime, SERGHERAERT, Christian
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.02.1999; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Chagas disease; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; combinatorial chemistry; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; protease inhibitor; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protein Conformation; Pyrroles - chemistry; Science & Technology; Serine Proteinase Inhibitors - chemistry; Structure-Activity Relationship; tetrahydroisoquinoleic acid; tripeptide; Trypanosoma cruzi; Trypanosoma cruzi - enzymology; protease inhibitor; LIGANDS; tripeptide; tetrahydroisoquinoleic acid; Chagas disease; combinatorial chemistry; PROLYL-ENDOPEPTIDASE; Trypanosoma cruzi; Protozoal disease; D stereoisomer; Peptides; Nitrogen heterocycle; Conformational analysis; Tripeptide; Combinatorial chemistry; Antiprotozoal agent; Structure activity relation; Parasiticid; Piperidine derivatives; Chemical synthesis; Trypanosomiasis; Kinetoplastida; Protozoa; Peptide library; Isoquinoline derivatives; Enzyme; Enzyme inhibitor; Parasitosis; Infection; Screening; Peptidases; Hydrolases; Peptide synthesis; Solid phase
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.47.194

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 15625 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.