Ligation Technologies for the Synthesis of Cyclic Peptides

Abstract

Cyclic peptides have been attracting a lot of attention in recent decades, especially in the area of drug discovery, as more and more naturally occurring cyclic peptides with diverse biological activities have been discovered. Chemical synthesis of cyclic peptides is essential when studying their structure−activity relationships. Conventional peptide cyclization methods via direct coupling have inherent limitations, like the susceptibility to epimerization at the C-terminus, poor solubility of fully protected peptide precursors, and low yield caused by oligomerization. In this regard, chemoselective ligation-mediated cyclization methods have emerged as effective strategies for cyclic peptide synthesis. The toolbox for cyclic peptide synthesis has been expanded substantially in the past two decades, allowing more efficient synthesis of cyclic peptides with various scaffolds and modifications. This Review will explore different chemoselective ligation technologies used for cyclic peptide synthesis that generate both native and unnatural peptide linkages. The practical issues and limitations of different methods will be discussed. The advance in cyclic peptide synthesis will benefit the biological and medicinal study of cyclic peptides, an important class of macrocycles with potentials in numerous fields, notably in therapeutics. CONTENTS

Long-range PEG stapling: macrocyclization for increased protein conformational stability and resistance to proteolysis

“…[1][2][3][4] Disulfide bonds can play this role in synthetic peptides or proteins; [5][6][7][8][9] however, correct disulfide connectivity sometimes requires creative protecting group strategies and the disulfides themselves are not stable in reducing environments, making disulfide-stapled peptides and proteins unsuitable as therapeutics with intracellular targets. Efforts to address these limitations have led to a growing number of chemoselective ligation reactions 10 (i.e., stapling reactions) that are tolerant of water and are selective for a particular reactive partner in the presence of diverse biological nucleophiles and electrophiles. Thiol alkyl- [11][12][13][14][15] or arylation 16 takes advantage of the nucleophilicity of Cys but results in thioether staples that are stable to reducing conditions.…”

CyClick Chemistry for the Synthesis of Cyclic Peptides

“…Themajor problems associated with current cyclization strategies are C-terminal epimerization, cyclooligomerization, and formation of linear dimers and trimers ( Figure 1a). [18][19][20][21][22] Consequently,t here is ag reat need to develop new synthetic methodologies that can circumvent the aforementioned limitations and provide an efficient strategy for easy access to av ariety of cyclic peptides.O ne approach to achieve this goal is to develop as trategy that could work in an exclusively intramolecular fashion. Currently,t here are no such methods available to achieve this goal.…”

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

“…More importantly, it is unnecessary to protect the side chains of amino acids because of the high chemoselectivity of chemical ligations. There are mainly three kinds of chemical ligation‐mediated methods popularly available for peptide cyclization right now: native chemical ligation, Ser/Thr ligation and KAHA ligation …”