Synthesis of prenylated peptides and peptide esters

Naider, Fred; Becker, Jeffrey M.

doi:10.1002/(sici)1097-0282(1997)43:1<3::aid-bip2>3.0.co;2-z

Cited by 42 publications

(31 citation statements)

References 58 publications

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“…First, the all trans double bonds of the prenyl groups are not stable to the acidic conditions necessary to remove standard t -butyl-based side-chain protecting groups used in Fmoc chemistry;40 exposure of isoprenoids to acidic conditions typically leads to complex mixtures of solvolyzed and rearranged products. Next, because the C -terminal methyl ester is necessary for activity, standard amide and acid SPPS resin linkages are not suitable for use in this synthesis.…”

Section: Resultsmentioning

confidence: 99%

“…This result supported our hypothesis that a fully protected a -factor sequence was necessary for successful oxidative cleavage. Alkylation of the cysteine thiol of 9 with farnesyl bromide, catalyzed by Zn 2+ 40 gave a -factor ( 1 ) (Scheme 2). Benzophenone analogues 2 and 3 were obtained by reaction of 9 with the corresponding allylic bromides under the same alkylation conditions.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of a-factor peptide from Saccharomyces cerevisiae and photoactive analogues via Fmoc solid phase methodology

Mullen

Kyro

Hauser

et al. 2011

Bioorganic & Medicinal Chemistry

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a-Factor from S. cerevisiae is a farnesylated dodecapeptide involved in mating. The molecule binds to a G-protein coupled receptor and hence serves as a simple system for studying the interactions between prenylated molecules and their cognate receptors. Here, we describe the preparation of a-factor and two photoactive analogues via Fmoc solid-phase peptide synthesis using hydrazinobenzoyl AM NovaGel™ resin; the structure of the synthetic a-factor was confirmed by MS-MS analysis and NMR; the structures of the analogues were confirmed by MS-MS analysis. Using a yeast growth arrest assay, the analogues were found to have activity comparable to a-factor itself.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis of a-factor peptide from Saccharomyces cerevisiae and photoactive analogues via Fmoc solid phase methodology

Mullen

Kyro

Hauser

et al. 2011

Bioorganic & Medicinal Chemistry

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“…In order to accommodate these modifications, two amino acids were added to the N -terminus, and a protection scheme that included three dimensions of orthogonality was chosen. Since the all- trans double bonds of the prenyl groups are not stable to the acidic final cleavage conditions used in Fmoc-based SPPS, these moieties were attached to the peptide in solution subsequent to cleavage from the resin 32. Also, to avoid scrambling the disulfide linkage amongst the two cysteines, penetratin was added last in the synthetic sequence.…”

Section: Discussionmentioning

confidence: 99%

Multifunctional Prenylated Peptides for Live Cell Analysis

et al. 2009

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Protein prenylation is a common post-translational modification present in eukaryotic cells. Many key proteins involved in signal transduction pathways are prenylated and inhibition of prenylation can be useful as a therapeutic intervention. While significant progress has been made in understanding protein prenylation in vitro, we have been interested in studying this process in living cells, including the question of where prenylated molecules localize. Here, we describe the synthesis and live cell analysis of a series of fluorescently labeled multifunctional peptides, based on the C-terminus of the naturally prenylated protein CDC42. A synthetic route was developed that features a key Acm to Scm protecting group conversion. This strategy was compatible with acid-sensitive isoprenoid moieties, and allowed incorporation of an appropriate fluorophore as well as a cell-penetrating sequence (penetratin). These peptides are able to enter cells through different mechanisms, depending on the presence or absence of the penetratin vehicle and the nature of the prenyl group attached. Interestingly, prenylated peptides lacking penetratin are able to enter cells freely through an energy-independent process, and localize in a perinuclear fashion. This effect extends to a prenylated peptide that includes a full “CAAX box” sequence (specifically, CVLL). Hence, these peptides open the door for studies of protein prenylation in living cells, including enzymatic processing and intracellular peptide trafficking. Moreover, the synthetic strategy developed here should be useful for the assembly of other types of peptides that contain acid sensitive functionalities.

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“…[16] The synthesis of N-acylated compounds follows established procedures of solid-phase chemistry, whereas only a few examples for the synthesis of S-palmitoylated peptides have been published. Thioesters are stable under the conditions required for the removal of acid-labile blocking functions, farnesyl and geranylgeranyl thioethers are not attacked at pH b 7, and myristoyl amides tolerate both reaction conditions.…”

Section: Synthesis Of Lipid-modified Peptides Containing One Lipid Groupmentioning

confidence: 99%

Linking the Fields—The Interplay of Organic Synthesis, Biophysical Chemistry, and Cell Biology in the Chemical Biology of Protein Lipidation

2000

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Research in the biological sciences has undergone a fundamental and dramatic change during the last decades. Whereas biology was more phenomenologically oriented for a long time, today many biological processes are investigated and understood in molecular detail. It has become evident that all biological phenomena have a chemical basis: Biology is based on chemical principles. In the past, this insight had led to the development of biochemistry, molecular biology, and modern pharmacology. Today it increasingly determines the manner in which various biological phenomena are studied. The tools provided by classical biological techniques often are not sufficient to address the prevailing issues in precise molecular detail. Instead, the strengths of both chemical and biological methodology have to be used. Several recent research projects have proven that combining the power of organic synthesis with cell biology may open up entirely new and alternative opportunities for the study of biological problems. In this review we summarize the successful interplay between three disciplines-organic synthesis, biophysics, and cell biology-in the study of protein lipidation and its relevance to targeting of proteins to the plasma membrane of cells in precise molecular detail. This interplay is highlighted by using the Ras protein as a representative example. The development of methods for the synthesis of Ras-derived peptides and fully functional Ras proteins, the determination of their biophysical properties, in particular the ability to bind to model membranes, and finally the use of synthetic Ras peptides and Ras proteins in cell biological experiments are addressed. The successful combination of these three disciplines has led to a better understanding of the factors governing the selective targeting of Ras and related lipid-modified proteins to the plasma membrane.

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Synthesis of prenylated peptides and peptide esters

Cited by 42 publications

References 58 publications

Synthesis of a-factor peptide from Saccharomyces cerevisiae and photoactive analogues via Fmoc solid phase methodology

Synthesis of a-factor peptide from Saccharomyces cerevisiae and photoactive analogues via Fmoc solid phase methodology

Multifunctional Prenylated Peptides for Live Cell Analysis

Linking the Fields—The Interplay of Organic Synthesis, Biophysical Chemistry, and Cell Biology in the Chemical Biology of Protein Lipidation

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