Synthesis of Peptides Containing C-Terminal Esters Using Trityl Side-Chain Anchoring

Applications to the Synthesis of C-Terminal Ester Analogs of the Saccharomyces cerevisiae Mating Pheromone a -Factor

Veronica Diaz-Rodriguez, Elena Ganusova, Todd M. Rappe, Jeffrey M. Becker, Mark D Distefano

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Peptides containing C-terminal esters are an important class of bioactive molecules that includes a-factor, a farnesylated dodecapeptide, involved in the mating of Saccharomyces cerevisiae. Here, results that expand the scope of solid-phase peptide synthetic methodology that uses trityl side-chain anchoring for the preparation of peptides with C-terminal cysteine alkyl esters are described. In this method, Fmoc-protected C-terminal cysteine esters are anchored to trityl chloride resin and extended by standard solid-phase procedures followed by acidolytic cleavage and HPLC purification. Analysis using a Gly-Phe-Cys-OMe model tripeptide revealed minimal epimerization of the C-terminal cysteine residue under basic conditions used for Fmoc deprotection. 1H NMR analysis of the unfarnesylated a-factor precursor peptide confirmed the absence of epimerization. The side-chain anchoring method was used to produce wild-type a-factor that contains a C-terminal methyl ester along with ethyl-, isopropyl-, and benzyl-ester analogs in good yield. Activity assays using a yeast-mating assay demonstrate that while the ethyl and isopropyl esters manifest near-wild-type activity, the benzyl ester-containing analog is ca. 100-fold less active. This simple method opens the door to the synthesis of a variety of C-terminal ester-modified peptides that should be useful in studies of protein prenylation and other structurally related biological processes.

Original languageEnglish (US)
Pages (from-to)11266-11274
Number of pages9
JournalJournal of Organic Chemistry
Volume80
Issue number22
DOIs
StatePublished - Nov 20 2015

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Pheromones
Yeast
Esters
Peptides
Cysteine
Assays
Purification
Resins
Nuclear magnetic resonance
Molecules

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Synthesis of Peptides Containing C-Terminal Esters Using Trityl Side-Chain Anchoring : Applications to the Synthesis of C-Terminal Ester Analogs of the Saccharomyces cerevisiae Mating Pheromone a -Factor. / Diaz-Rodriguez, Veronica; Ganusova, Elena; Rappe, Todd M.; Becker, Jeffrey M.; Distefano, Mark D.

In: Journal of Organic Chemistry, Vol. 80, No. 22, 20.11.2015, p. 11266-11274.

Research output: Contribution to journalArticle

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