Cyclic Peptide Synthesis

Kirkland Peptide offers various types of cyclic peptide synthesis using topologies such as: head-to-tail, side-chain-to-side-chain, head-to-side-chain, and side-chain-to-tail.

Introduction

Kirkland Peptide offers various types of cyclic peptide synthesis using topologies such as: head-to-tail, side-chain-to-side-chain, head-to-side-chain, and side-chain-to-tail. Ring closure in side chain to side chain cyclic peptides can be attained by disulfide or amide bond
formation between sulfhydryl groups or other appropriate methods. Cyclic peptide synthesis is useful in developing peptidomimetic agents from diagnostic to immunosuppressant toxins and drugs for therapeutic research. Cyclic peptides are stable peptide analogs with strong conformational stability and biostability. Cyclic peptides metabolize slower due to their higher resistance to protease. They also have longer acting depot effects than their corresponding linear counterparts. They can be used to mimic the structure of biologicaly active peptides (e.g. peptide hormones) and bind drug targets in vivo.

Cyclic peptide synthesis has proven to be useful for several applications:

  • Structural studies of peptides
  • Investigation of peptides and their biological function
  • Enzyme functions and kinetics

Kirkland Peptide provides high quality cyclic peptide synthesis services under strict Quality
Control. Each peptide is quality checked using MALDI-TOF mass spectrometry and HPLC
analysis at each stage of the production cycle.

Peptide Cyclization Synthesis Services

Backbone to backbone cyclization strategies through the formation of an amide bond between
the N-terminal and C-terminal amino acid residues.

Cyclization of side chain amino acids such as:

  • Formation of disulfide bridges between cysteine (homocycsteine)
  • Formation of lactam bridges between glutamic/aspartic acid and lysine residues
  • Formation of lactone and thiolactone bridges between amino acid containing carboxyl, hydroxyl or mercapto functional groups.
  • Formation of thioether or ether bridges between the amino acids containing hydroxyl or mercapto functional groups and other special methods.

Depending on the cyclization position, there are several methods to synthesize cyclic peptides:

  • head-to-tail,
  • side-chain-to-side-chain,
  • head-to-side-chain
  • side-chain-to-tail (see figure below)

While head-to-tail cycles are usually formed by amide bond formation, side-chain-to-side-chain cycles are most often synthesized via Cys-Cys or amide bond formation.

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Disulfide Bridge Cys-Cys Thiol Oxidation

Peptide disulfide bridge readily synthesizes two thiol (SH) groups from the side chain of
cysteine or cysteine analogs. Our unique synthesis strategy enables us to offer either specific
intra or intermolecular oxidation using appropriate protecting group chemistry to prevent
undesired linkage. The reaction can be followed by HPLC and MALDI TOF mass spectrometry
with the linear peptide losing two mass units (2H) on cyclization.

In General, disulfide bridge can be formed as follows:

Intermolecular (two peptide molecules are linked via the disulfide bridge), resulting in either 


    •  homodimers (two identical peptides) or
    •  heterodimers (two different peptides).
    •   Intramolecular (cyclization within one peptide molecule)
While head-to-tail cyclization is usually formed by using an amide bond formation, side-chain-to-side-chain peptide cyclization is most often synthesized via cys-cys or amide bond formation.

 

Peptide cyclization using cys-cys has limited stability in reductive conditions. Therefore, projects involving drug discovery, commonly use cys-cys cyclized peptides for initial screening and optimization followed by replacement of disulfide bonds with more stable bonds.

Peptides with two or more disulfide bridges require selective protection of the cysteine side chains to ensure that the correct disulfide bridges are formed. We provide peptides with up to 4 disulfide bonds in one peptide using site-specific orthogonal chemistry or thermodynamic stability methods. Contact us to discuss your project details.

Amide Bond formation, Lactam Formation

Cyclic peptides can also be synthesized by linking the amino (N) terminus of the peptide to the carboxyl (C) terminus via an amide bond. The amino side chains of Lys and Orn and the carboxyl side chains of Asp and Glu can also be used to construct cyclic peptides via an amide bond. Amide bonds are more chemically stable than disulfide bridge. Depending on functional groups of a peptide, cyclic peptide synthesis can be formed in four different ways:

  •  Head-to-tail between N-terminus and C-terminus
  •  Head-to-side chain between N-terminus and an internal COOH (e.g. the B-COOH-group of Asp or y-COOH-group of Glu)
  •  Side chain-to-tail between internal NH2s and C-terminus (e.g. the E-NH2—group of Lys) 
  •  Side-chain-to-side-chain between an internal NH2 and an internal COOH (e.g. the E.-NH2—group of Lys with either the 13-COOH-group of Asp or y-COOH-group of Glu)

As with disulfide cys-cys cyclization, amide cyclization is also limited by the challenges of dimerization, undesirable side reactions such as racemization or peptide capping by coupling reagents. For an effective head-to tail cyclization, it is important to carefully select cyclization site, reagent, and optimized cyclization conditions. Biosynthesis has extensive experience in synthesizing amide cyclic peptides with a high success rate.

Stapled Peptide Synthesis

Cysteines are common structural motifs in naturally occurring peptides such as neurotoxins, somatostatin and insulin. These disulfide bridges are readily reduced to their acyclic thiol form in an intracellular environment. This challenge can be overcome by using hydrocarbon-stapled peptide synthesis. These peptides are capable of forming stable alpha helical structures as a result of “hydrocarbon stapling” (1,2). Stapled peptides have a chemically locked conformational structure which can mimic the molecular structures that are typically found at the interface of protein-protein  interactions. When locked into this stable configuration, constrained peptides are able to penetrate cells and can exert their effect on intracellular protein targets. The large surface area of peptides gives them an advantage over small molecules in their ability to disrupt specific signaling pathways by inhibiting targeted protein-protein interactions. Hydrocarbon stapling is a useful strategy in researching experimental and therapeutic modulation of protein-protein interactions as well as in-vivo pharmacokinetics studies.

References:

  • Walensky, LD. et al. Science 305, 1466 (2004)
  • Schafmeister, CE. et al. J. Am. Chem. Soc. 122, 5891 (2002)

Click Chemistry for peptide cyclization

The cyclization technique increases peptide molecules’ potency and in vivo half-life by locking their conformation. In addition to disulfide and amide cyclizations, many other cyclization methods are available at Scrippspeptide. Clickable functional groups can be incorporated into synthesized peptides using different combinations of protected amino acids modified with an alkyne group, followed by a click reaction with an azido acid. The resulting peptides are detached  from the resin to give triazole-containing peptides. Post-synthesis modification allows the introduction of these functional groups to produce structurally constrained peptides.Scrippspeptide scientists have used click reactions to prepare several different peptide cyclizations.

Please note:

Kirkland Peptide does not offer Copper based Click Chemistry, we only offer Copper free click chemistry. For Copper based Click Chemistry, please contact baseclick GMBH.

Click-Chemitry-peptide-cyclization
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