Solid-phase synthesis of a farnesylated CaaX peptide library: inhibitors of the Ras CaaX endoprotease.
A solid-phase method, based on Kaiser's p-benzophenone oxime resin, was developed for the synthesis of a series of N-acetyl-S-(E, E-farnesylated) Ca(1)a(2)X tetrapeptides as potential inhibitors of recombinant Ras and a-factor converting enzyme (RCE). N-Acetyl-S-(E, E-farnesyl)-L-cysteine was coupled to resin-bound a(1)a(2) dipeptide using HOBt/DCC activation in conjunction with N-BOC chemistry. The protected farnesylated tripeptide was cleaved from the resin with simultaneous addition of the X residue by treating the resin-bound farnesylated Ca(1)a(2) tripeptide with L-amino acid benzyl ester tosylates under mildly acidic conditions. The benzyl ester was saponified, and the resulting carboxylate precipitated by ether to afford a library of tetrapeptides as a mixture of diastereomers at the cysteine center. The peptides were evaluated as inhibitors of recombinant yeast RCE endoprotease (yRCE) to obtain information about the affinity of the enzyme for the a(1)a(2)X portion of the Ca(1)a(2)X moiety.
Dolence
E K
EK
Department of Chemistry, University of Utah, 315 South 1400 East, Room 2020, Salt Lake City, Utah 84112-0850, USA.
Dolence
J M
JM
Poulter
C D
CD
D000595:Amino Acid Sequence; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D010450:Endopeptidases / Q000378:metabolism*; D007202:Indicators and Reagents; D008666:Metalloendopeptidases; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019151:Peptide Library; D043484:Proprotein Convertases; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017368:Protein Prenylation; D011499:Protein Processing, Post-Translational; D029701:Saccharomyces cerevisiae Proteins; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D009842:Oligopeptides; D019151:Peptide Library; D011480:Protease Inhibitors; D029701:Saccharomyces cerevisiae Proteins; D010450:Endopeptidases; D043484:Proprotein Convertases; C105193:RCE1 protein, S cerevisiae; D008666:Metalloendopeptidases