A Comprehensive One-Pot Synthesis of Protected Cysteine and Selenocysteine SPPS Derivatives

2014 ◽  
Vol 21 (12) ◽  
pp. 1257-1264
Author(s):  
Stevenson Flemer
Keyword(s):  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Reduction Process ◽  
Building Blocks ◽  
High Yield ◽  
One Pot ◽  
Peptide Models ◽  
Direct Use ◽  
Proof Of Principle ◽  
Subsequent Incorporation

A proof-of-principle methodology is presented in which all commercially-available cysteine (Cys) and selenocysteine (Sec) solid phase peptide synthesis (SPPS) derivatives are synthesized in high yield from easily prepared protected dichalcogenide precursors. A Zn-mediated biphasic reduction process applied to a series of four bis-Nα-protected dichalcogenide compounds allows facile conversion to their corresponding thiol and selenol intermediates followed by insitu S- or Se-alkylation with various electrophiles to directly access twenty one known Cys and Sec SPPS derivatives. Most of these derivatives were able to be precipitated in crude form out of petroleum ether in sufficient purity for direct use as peptide building blocks. Subsequent incorporation of these derivatives into peptide models nicely illustrates their viability and applicability toward SPPS.

scholarly journals Stereorandomization as a Method to Probe Peptide Bioactivity

2020 ◽  
Author(s):  
Thissa N. Siriwardena ◽  
Bee-Ha Gan ◽  
Thilo Köhler ◽  
Christian van Delden ◽  
Sacha Javor ◽  
...  
Keyword(s):  
Cyclic Peptide ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Therapeutic Index ◽  
Building Blocks ◽  
Polymyxin B ◽  
High Yield ◽  
Peptide Antibiotic ◽  
Disruptive Effect ◽  
Peptide Dendrimers

<p>Solid-phase peptide synthesis (SPPS) is usually performed with optically pure building blocks to prepare peptides as single enantiomers. Herein we report that SPPS using racemic amino acids provides stereorandomized (<i>sr</i>) peptides, containing up to billions of different stereoisomers,<a> </a>as well-defined single HPLC peak, single mass products with high yield, which can be used to investigate peptide bioactivity. To exemplify our method, we show that stereorandomization abolishes the membrane disruptive effect of α-helical amphiphilic antimicrobial peptides but preserves their antibiofilm effect, implying different mechanisms involving folded versus disordered conformations. For antimicrobial peptide dendrimers by contrast, stereorandomization preserves antibacterial, membrane disruptive and anti-biofilm effects but reduces hemolysis and cytotoxicity, thereby increasing their therapeutic index. Finally, we identify partially stereorandomized analogs of the last resort cyclic peptide antibiotic polymyxin B with preserved antibacterial activity but lacking membrane disruptive and lipopolysaccharide neutralizing activity, pointing to the existence of additional targets.</p>

scholarly journals Stereorandomization as a Method to Probe Peptide Bioactivity

2020 ◽  
Author(s):  
Thissa N. Siriwardena ◽  
Bee-Ha Gan ◽  
Thilo Köhler ◽  
Christian van Delden ◽  
Sacha Javor ◽  
...  
Keyword(s):  
Cyclic Peptide ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Therapeutic Index ◽  
Building Blocks ◽  
Polymyxin B ◽  
High Yield ◽  
Peptide Antibiotic ◽  
Disruptive Effect ◽  
Peptide Dendrimers

<p>Solid-phase peptide synthesis (SPPS) is usually performed with optically pure building blocks to prepare peptides as single enantiomers. Herein we report that SPPS using racemic amino acids provides stereorandomized (<i>sr</i>) peptides, containing up to billions of different stereoisomers,<a> </a>as well-defined single HPLC peak, single mass products with high yield, which can be used to investigate peptide bioactivity. To exemplify our method, we show that stereorandomization abolishes the membrane disruptive effect of α-helical amphiphilic antimicrobial peptides but preserves their antibiofilm effect, implying different mechanisms involving folded versus disordered conformations. For antimicrobial peptide dendrimers by contrast, stereorandomization preserves antibacterial, membrane disruptive and anti-biofilm effects but reduces hemolysis and cytotoxicity, thereby increasing their therapeutic index. Finally, we identify partially stereorandomized analogs of the last resort cyclic peptide antibiotic polymyxin B with preserved antibacterial activity but lacking membrane disruptive and lipopolysaccharide neutralizing activity, pointing to the existence of additional targets.</p>

scholarly journals Pyrrole-Mediated Peptide Cyclization Identified through Genetically Reprogrammed Peptide Synthesis

Biomedicines ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 99 ◽  
Author(s):  
Klaas Decoene ◽  
Willem Vannecke ◽  
Toby Passioura ◽  
Hiroaki Suga ◽  
Annemieke Madder
Keyword(s):  
Peptide Synthesis ◽  
Cyclic Peptide ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Screening Method ◽  
In Vitro Translation ◽  
Side Chain ◽  
One Pot ◽  
Depth Analysis

Flexible in vitro translation (FIT) was used as a screening method to uncover a new methodology for peptide constraining based on the attack of a nucleophilic side-chain functionality onto an oxidized furylalanine side chain. A set of template peptides, each containing furylalanine as furan-modified amino acid and a nucleophilic residue (Cys, His, Lys, Arg, Ser, or Tyr), was produced through FIT. The translation mixtures were treated with N-bromosuccinimide (NBS) to achieve selective furan oxidation and subsequent MALDI analysis demonstrated Lys and Ser as promising residues for cyclisation. Solid-phase peptide synthesis (SPPS) was used to synthesize suitable amounts of material for further in-depth analysis and characterisation. It was found that in the case of the peptide containing lysine next to a furylalanine residue, a one-pot oxidation and reduction reaction leads to the generation of a cyclic peptide featuring a pyrrole moiety as cyclisation motif, resulting from the attack of the lysine side chain onto the oxidized furylalanine side chain. Structural evidence was provided via NMR and the generality of the methodology was explored. We hereby expand the scope of our previously developed furan-based peptide labeling and crosslinking strategy.

scholarly journals Reinvestigation of a Critical Reductive Amination Step Leads to an Optimized Protocol for the Synthesis of N-2-Hydroxybenzylcysteine Peptide Crypto-Thioesters

2020 ◽  
Author(s):  
Skander Abboud ◽  
Vincent AUCAGNE
Keyword(s):  
Peptide Synthesis ◽  
Reaction Mechanisms ◽  
Reductive Amination ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Building Blocks ◽  
Native Chemical Ligation ◽  
Chemical Ligation ◽  
Optimized Protocol ◽  
Depth Study

An in-depth study of the Fmoc-based solid phase peptide synthesis of N-Hnb-Cys crypto-thioester peptides, advantageous building blocks for the native chemical ligation-based synthesis of proteins, led to the identification of epimerized and imidazolidinone side products formed during a key reductive amination step. The understanding of the underlying reaction mechanisms was crucial for the developement of an automatable optimized synthetic protocol.

scholarly journals Development of oxetane modified building blocks for peptide synthesis

2020 ◽  
Vol 18 (28) ◽  
pp. 5400-5405 ◽  
Author(s):  
Stefan Roesner ◽  
Jonathan D. Beadle ◽  
Leo K. B. Tam ◽  
Ina Wilkening ◽  
Guy J. Clarkson ◽  
...  
Keyword(s):  
Peptide Synthesis ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Building Blocks

The synthesis and use of oxetane modified dipeptide building blocks in solution and solid-phase peptide synthesis (SPPS) is reported.

Ferroelectric-Specific Peptides as Building Blocks for Bio-Inorganic Devices

2006 ◽  
Vol 944 ◽  
Author(s):  
Brian Dennis Reiss ◽  
Leonidas Ocola ◽  
Orlando Auciello ◽  
Millicent A. Firestone
Keyword(s):  
Solid Phase ◽  
Sol Gel ◽  
Solid Phase Peptide Synthesis ◽  
Peptide Binding ◽  
Building Blocks ◽  
Inorganic Materials ◽  
X Ray ◽  
Long Term Stability ◽  
Functional Composites ◽  
Nanofluidic Devices

ABSTRACTThe integration of biomolecules with inorganic materials to create functional composites represents a critical step in the development of next-generation biosensors, micro/nanofluidic devices, and biochips that require a combination of abiotic (inorganics) and biotic (proteins, DNA, antibodies) components. Toward this end, we have previously applied combinatorial phage display techniques to identify a constrained heptapeptide sequence (CISLLHSTC) that selectively binds to a perovskite ferroelectric (MOCVD-deposited lead zirconium titanate, PZT). In this work, we examine the binding of this heptapeptide sequence, prepared by solid phase peptide synthesis to sol-gel PZT. In particular, the surface roughness has been examined and the long-term stability of the PZT films in biological buffered aqueous solutions by atomic force microscopy, X-ray diffraction and P-E hysteresis loop. In addition, the selectivity of the peptide binding to PZT has been determined by immunofluorescence microscopy and the nature of peptide binding to the PZT surface is probed by X-ray photoemission spectroscopy.

scholarly journals Facile solid phase peptide synthesis with a Re-lysine conjugate generated via a one-pot procedure

2014 ◽  
Vol 43 (30) ◽  
pp. 11452-11455 ◽  
Author(s):  
Kullapa Chanawanno ◽  
Joel Caporoso ◽  
Vinay Kondeti ◽  
Sailaja Paruchuri ◽  
Thomas C. Leeper ◽  
...  
Keyword(s):  
Schiff Base ◽  
Peptide Synthesis ◽  
Solid Phase ◽  
Vascular Endothelial Cells ◽  
Solid Phase Peptide Synthesis ◽  
Vascular Endothelial ◽  
One Pot ◽  
Formation Reaction ◽  
Schiff Base Formation ◽  
Base Formation

We have synthesized a Re(CO)3-modified lysine via a one-pot Schiff base formation reaction that can be used in the solid phase peptide synthesis of peptides, and demonstrated uptake into human umbilical vascular endothelial cells.

scholarly journals Traceless Click-Assisted Native Chemical Ligation Enabled by Protecting Dibenzocyclooctyne from Acid-Mediated Rearrangement with Copper(I)

2020 ◽  
Author(s):  
Patrick Erickson ◽  
James Fulcher ◽  
Michael Kay
Keyword(s):  
Synthetic Peptides ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Ribosomal Subunit ◽  
Side Reaction ◽  
Native Chemical Ligation ◽  
One Pot ◽  
Direct Production ◽  
Chemical Ligation ◽  
Peptide Cleavage

<div><div><div><p>Chemoselective ligation reactions, such as native chemical ligation (NCL), enable the assembly of synthetic peptides into proteins. However, the scope of proteins accessible to total chemical synthesis is limited by ligation efficiency. Sterically hindered thioesters and poorly soluble peptides can undergo incomplete ligations, leading to challenging purifications with low yields. This work describes a new method, ClickAssisted NCL (CAN), which overcomes these barriers. In CAN, peptides are modified with traceless “helping hand” lysine linkers that enable addition of dibenzocyclooctyne (DBCO) and azide handles for strain-promoted alkyne-azide cycloaddition (SPAAC) reactions. This cycloaddition templates the peptides to increase their effective concentration and greatly accelerate ligation kinetics. After ligation, mild hydroxylamine treatment tracelessly removes the linkers to afford the native ligated peptide. Although DBCO is incompatible with standard Fmoc solid-phase peptide synthesis (SPPS) due to an acid-mediated rearrangement that occurs during peptide cleavage, we demonstrate that copper(I) protects DBCO from this side reaction, enabling direct production of DBCO-containing synthetic peptides. Excitingly, low concentrations of triazole-linked model peptides reacted ~1,200-fold faster than predicted for non-templated control ligations, which also accumulated many side products due to the long reaction time. Using the E. coli ribosomal subunit L32 as a model protein, we further demonstrate that the SPAAC, ligation, desulfurization, and linker cleavage steps can be performed in a one-pot fashion. CAN will be useful for overcoming ligation challenges to expand the reach of chemical protein synthesis.</p></div></div></div>

A silyl ether-protected building block for O-GlcNAcylated peptide synthesis to enable one-pot acidic deprotection

2021 ◽  
Vol 19 (37) ◽  
pp. 8014-8017
Author(s):  
Bingjia Yan ◽  
Wenyi Li ◽  
Christian P. R. Hackenberger
Keyword(s):  
Peptide Synthesis ◽  
Building Block ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Silyl Ether ◽  
One Pot

In this report, we introduce a novel building block for Fmoc/tBu solid phase peptide synthesis (SPPS) of β-linked O-GlcNAcylated peptides.

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