scholarly journals Deprotection Strategies for Thioimidates During Fmoc Solid-Phase Peptide Synthesis: A Safe Route to Thioamides

2019 ◽  
Author(s):  
luis camacho III ◽  
Yen Nguyen ◽  
john turner ◽  
Brett VanVeller
Keyword(s):  
Peptide Synthesis ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Peptide Folding ◽  
Protecting Group ◽  
Flammable Gas ◽  
Biophysical Probes ◽  
Complete Regeneration

Thioamides are important biophysical probes of peptide folding, but are prone to alpha-C epimerization during Fmoc solid-phase peptide synthesis. The stereochemical integrity of thioamide-containing peptides can be dramatically improved by protecting the thioamide as a thioimidate during synthesis. A drawback of this approach, however, is that once synthesis of the peptide is complete, regeneration of the thioamide requires the toxic, corrosive, and flammable gas H2S. This work examines several approaches to supplant H2S as a deprotection reagent in favor of a safer and more convenient alternative. Ultimately, a new application of the 4-azidobenzyl protecting group to thioamides was found to provide the most suitable means of both protection of alpha-C stereochemistry and conversion back to thioamide.

scholarly journals Deprotection Strategies for Thioimidates During Fmoc Solid-Phase Peptide Synthesis: A Safe Route to Thioamides

2019 ◽  
Author(s):  
luis camacho III ◽  
Yen Nguyen ◽  
john turner ◽  
Brett VanVeller
Keyword(s):  
Peptide Synthesis ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Peptide Folding ◽  
Protecting Group ◽  
Flammable Gas ◽  
Biophysical Probes ◽  
Complete Regeneration

Thioamides are important biophysical probes of peptide folding, but are prone to alpha-C epimerization during Fmoc solid-phase peptide synthesis. The stereochemical integrity of thioamide-containing peptides can be dramatically improved by protecting the thioamide as a thioimidate during synthesis. A drawback of this approach, however, is that once synthesis of the peptide is complete, regeneration of the thioamide requires the toxic, corrosive, and flammable gas H2S. This work examines several approaches to supplant H2S as a deprotection reagent in favor of a safer and more convenient alternative. Ultimately, a new application of the 4-azidobenzyl protecting group to thioamides was found to provide the most suitable means of both protection of alpha-C stereochemistry and conversion back to thioamide.

scholarly journals Automated solid-phase peptide synthesis to obtain therapeutic peptides

2014 ◽  
Vol 10 ◽  
pp. 1197-1212 ◽  
Author(s):  
Veronika Mäde ◽  
Sylvia Els-Heindl ◽  
Annette G Beck-Sickinger
Keyword(s):  
Peptide Synthesis ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Protecting Group ◽  
Drug Candidates ◽  
Tremendous Progress ◽  
Pharmacokinetic Properties ◽  
Critical Issues ◽  
Therapeutic Peptides ◽  
Automated Methods

The great versatility and the inherent high affinities of peptides for their respective targets have led to tremendous progress for therapeutic applications in the last years. In order to increase the drugability of these frequently unstable and rapidly cleared molecules, chemical modifications are of great interest. Automated solid-phase peptide synthesis (SPPS) offers a suitable technology to produce chemically engineered peptides. This review concentrates on the application of SPPS by Fmoc/t-Bu protecting-group strategy, which is most commonly used. Critical issues and suggestions for the synthesis are covered. The development of automated methods from conventional to essentially improved microwave-assisted instruments is discussed. In order to improve pharmacokinetic properties of peptides, lipidation and PEGylation are described as covalent conjugation methods, which can be applied by a combination of automated and manual synthesis approaches. The synthesis and application of SPPS is described for neuropeptide Y receptor analogs as an example for bioactive hormones. The applied strategies represent innovative and potent methods for the development of novel peptide drug candidates that can be manufactured with optimized automated synthesis technologies.

Pyruvoyl, a novel amino protecting group on the solid phase peptide synthesis and the peptide condensation reaction

2009 ◽  
Vol 50 (7) ◽  
pp. 818-821 ◽  
Author(s):  
Hidekazu Katayama ◽  
Takumi Utsumi ◽  
Chinatsu Ozawa ◽  
Yuko Nakahara ◽  
Hironobu Hojo ◽  
...  
Keyword(s):  
Peptide Synthesis ◽  
Solid Phase ◽  
Condensation Reaction ◽  
Solid Phase Peptide Synthesis ◽  
Protecting Group

scholarly journals Revisiting NO2 as Protecting Group of Arginine in Solid-Phase Peptide Synthesis

2020 ◽  
Vol 21 (12) ◽  
pp. 4464
Author(s):  
Mahama Alhassan ◽  
Ashish Kumar ◽  
John Lopez ◽  
Fernando Albericio ◽  
Beatriz G. de la Torre
Keyword(s):  
Peptide Synthesis ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Side Reaction ◽  
Reducing Agent ◽  
Protecting Groups ◽  
Side Chain ◽  
Protecting Group ◽  
Mild Acid

The protection of side-chain arginine in solid-phase peptide synthesis requires attention since current protecting groups have several drawbacks. Herein, the NO2 group, which is scarcely used, has been revisited. This work shows that it prevents the formation of δ-lactam, the most severe side-reaction during the incorporation of Arg. Moreover, it is stable in solution for long periods and can be removed in an easy-to-understand manner. Thus, this protecting group can be removed while the protected peptide is still anchored to the resin, with SnCl2 as reducing agent in mild acid conditions using 2-MeTHF as solvent at 55 °C. Furthermore, we demonstrate that sonochemistry can facilitate the removal of NO2 from multiple Arg-containing peptides.

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