Exploring the stereochemical requirements for protease inhibition by ureidopeptides

• Published in: The journal of peptide research Vol. 65; no. 3; pp. 352 - 354
• Main Authors: Barth, B.S., Myers, A.C., Lipton, M.A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.03.2005; Wiley
• Subjects: Biochemical Research Methods; Biochemistry & Molecular Biology; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; human immunodeficiency virus-1 protease; inhibitor; Life Sciences & Biomedicine; peptide; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Protein Conformation; Science & Technology; substrate analog; urea; Urea - chemistry; substrate analog; peptide; inhibitor; CONVERSION; AMINES; human immunodeficiency virus-1 protease; urea; AMIDES
• DOI: 10.1111/j.1399-3011.2005.00224.x
• ISSN: 1397-002X

:  A novel ‘ureidopeptide’ substrate analog inhibitor of the HIV‐1 protease, created by substitution of a urea for the scissile amide bond of a hexapeptide substrate, was synthesized and tested for inhibition of HIV‐1 protease. This inhibitor was designed as a stereochemical mutant of an earlier ureidopeptide inhibitor in which the P1′ phenylalanine residue was changed from an l‐isomer to a d‐isomer. This was done in an attempt to increase binding to the enzyme by compensating for a lengthening of the peptide backbone. The inhibitor was synthesized from two protected tripeptide precursors using an oxidative Hoffmann rearrangement of a C‐terminal peptide amide. The new inhibitor was found to inhibit HIV‐1 protease with an observed IC50 of 47 μm.