Exploring the stereochemical requirements for protease inhibition by ureidopeptides.
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 IC(50) of 47 mum.
Barth
B S
BS
Department of Chemistry, Purdue University, West Lafayette, IN 47907-2084, USA.
Myers
A C
AC
Lipton
M A
MA
D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D014508:Urea / Q000737:chemistry*
D017320:HIV Protease Inhibitors; D010455:Peptides; D014508:Urea