Side Reactions in Peptide Synthesis

Yi Yang

• Publisher: Academic Press
• Year: 2015
• Print ISBN: 9780128010099
• eBook ISBN: 9780128011812
• Topic: Physical Sciences
• Subtopic: Biochemistry

Side Reactions in Peptide Synthesis, based on the author's academic and industrial experience, and backed by a thorough review of the current literature, provides analysis of, and proposes solutions to, the most frequently encountered side reactions during peptide and peptidomimetic synthesis.This valuable handbook is ideal for research and process chemists working with peptide synthesis in diverse settings across academic, biotech, and pharmaceutical research and development.While peptide chemistry is increasingly prevalent, common side reactions and their causes are often poorly understood or anticipated, causing unnecessary waste of materials and delay.Each chapter discusses common side reactions through detailed chemical equations, proposed mechanisms (if any), theoretical background, and finally, a variety of possible solutions to avoid or alleviate the specified side reaction.- Provides a systematic examination on how to troubleshoot and minimize the most frequent side reactions in peptide synthesis- Gives chemists the background information and the practical tools they need to successfully troubleshoot and improve results- Includes optimization-oriented analysis of side reactions in peptide synthesis for improved industrial process development in peptidyl API (active pharmaceutical ingredient) production- Answers the growing, global need for improved, replicable processes to avoid impurities and maintain the integrity of the end product.- Presents a thorough discussion of critical factors in peptide synthesis which are often neglected or underestimated by chemists- Covers solid phase and solution phase methodologies, and provides abundant references for further exploration

Chapter 1

Peptide Fragmentation/Deletion Side Reactions

Abstract

Due to the inherent attributes of certain peptide individuals they could undergo a variety of fragmentation processes during synthesis, purification or even storage. Fragmentation could selectively address peptides with characteristic sequences like N-terminal N-Ac-N-alkyl moiety, N-acyl-N-alkyl-Aib-Xaa- bond, -Asp-Pro-, N-terminal His-Pro-Xaa-moiety, C-terminal N-Me-Xaa, N-terminal FITC, thioamide bond, and guanidinyl group on Arg side chain, etc. Moreover, utilization of isodipeptide Boc-Ser/Thr(Fmoc-Xaa)-OH as the building block for peptide synthesis could result in the formation of des-Ser/Thr impurity. On top of these specific cases DKP formation could also affect general peptide assembly that leads to the deletion of affected dipeptide moiety from the parental peptide sequence. The occurrence of these fragmentation/deletion side reactions on peptide materials could decrease the manufacturing yield, cause challenges for the down-stream peptide purification, and affect peptide stability upon processing and/or storage. Phenomenon and mechanism of common fragmentation/deletion in peptide synthesis are described in this chapter. Corresponding solutions to minimize these side reactions are proposed.

Keywords

peptide fragmentation/deletion

N-Ac-N-alkyl

N-acyl-N-alkyl-Aib-Xaa-

-Asp-Pro-

His-Pro-Xaa-

C-terminal N-Me-Xaa

N-terminal FITC

thioamide

Boc-Ser/Thr(Fmoc-Xaa)-OH

DKP formation

Due to the inherent attributes of certain peptide individuals they could undergo a variety of fragmentation processes during synthesis, purification or even storage. Fragmentation could selectively address peptides with characteristic sequences like N-terminal N-Ac-N-alkyl moiety, N-acyl-N-alkyl-Aib-Xaa- bond, -Asp-Pro-, N-terminal His-Pro-Xaa- moiety, C-terminal N-Me-Xaa, N-terminal FITC, thioamide bond and guanidinyl group on Arg side chain, etc. Moreover, utilization of isodipeptide Boc-Ser/Thr(Fmoc-Xaa)-OH as the building block for peptide synthesis could result in the formation of des-Ser/Thr impurity. On top of these specific cases DKP formation could also affect general peptide assembly that leads to the deletion of affected dipeptide moiety from the parental peptide sequence. The occurrence of these fragmentation/deletion side reactions on peptide materials could decrease the manufacturing yield, cause challenges for the down-stream peptide purification, and affect peptide stability upon processing and/or storage. Phenomenon and mechanism of common fragmentation/deletion in peptide synthesis are described in this chapter. Corresponding solutions to minimize these side reactions are proposed.

1.1. Acidolysis of peptides containing N-Ac-N-alkyl-Xaa motif

Peptides with a motif of N-Ac-N-alkyl-Xaa sequence at the N-terminus...

Table of contents

• Cover
• Title page
• Table of Contents
• Copyright
• Dedication
• Preface
• Chapter 1: Peptide Fragmentation/Deletion Side Reactions
• Chapter 2: β-Elimination Side Reactions
• Chapter 3: Peptide Global Deprotection/Scavenger-Induced Side Reactions
• Chapter 4: Peptide Rearrangement Side Reactions
• Chapter 5: Side Reactions Upon Amino Acid/Peptide Carboxyl Activation
• Chapter 6: Intramolecular Cyclization Side Reactions
• Chapter 7: Side Reactions on Amino Groups in Peptide Synthesis
• Chapter 8: Side Reactions on Hydroxyl and Carboxyl Groups in Peptide Synthesis
• Chapter 9: Peptide Oxidation/Reduction Side Reactions
• Chapter 10: Redundant Amino Acid Coupling Side Reactions
• Chapter 11: Peptide Racemization
• Chapter 12: Side Reactions in Peptide Phosphorylation
• Chapter 13: Cys Disulfide-Related Side Reactions in Peptide Synthesis
• Chapter 14: Solvent-Induced Side Reactions in Peptide Synthesis
• Appendix I: Molecular Weight Deviation of Peptide Impurity
• Appendix II: List of Abbreviations
• Subject Index