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Macrocyclization

Protein-protein and protein-peptide interactions play critical roles in all types of cellular processing. Peptides are natural partners of proteins and as ligands, bind to proteins with high affinity due to their capacity to adapt to the often flexible protein surface. While peptides offer biocompatibility due to their similarity to proteins, as drug candidates they suffer drawbacks that include low plasma bioavailability, instability from proteolytic enzymes, and poor passive membrane permeability. Some success has been achieved with linear peptides, particularly with peptides that maintain α-helical secondary structures. These motifs can be introduced to stabilized α-helical motifs by common 'peptide-stapling' approaches, but stapled peptides can suffer from low bioactivity and poor solubility. Another strategy to improve peptide drugability has been to modify peptides by macrocyclization.

CPC Scientific specializes in the synthesis of complex peptide macrocycles and has the expertise to carryout a variety of ring-closure methodologies. We routinely synthesize peptide macrocycles with the following bond types:

  • Multiple, Regioselective disulfide bridges
    (Cys-Cys, Pen-Cys, and Pen-Pen)
  • Amide bond cyclizations (lactam)
  • Head-to-tail, head-to-tail, head-to-sidechain, sidechain-to-tail, sidechain-to-sidechain
  • Backbone-to-backbone, backbone-to-sidechain, backbone-to-head, and backbone-to-tail
  • Thioether bridges (see figure on right)
  • hydrocarbon-stapled peptides
  • Copper-catalyzed azide-alkyne cycloaddition (Click Chemistry)
peptide macrocycle types

X = S-S (disulfide bridge)
X = NH-CO (lactam bridge, amide bond)
X = S (thioether bridge, sulfide bridge)
X = O-CO (lactone bridge, depsipeptide)
X = CH=CH (alkene bridge, hydrocarbon stapled)
Y = NH (lactam bridge, amide bond)
Y = O (depsipeptide)

Complex Macrocycles: Lactam Homodimer

heterodimeric peptide macrocycles

Wang, Weixun, Nykia D. Walker, Li-Ji Zhu, Weizhen Wu, Lan Ge, David E. Gutstein, Nathan A. Yates et al. "Quantification of circulating D-dimer by peptide immunoaffinity enrichment and tandem mass spectrometry." Analytical chemistry 84, no. 15 (2012): 6891-6898.

Custom Peptide Synthesis Macrocycles

Chatterjee, Samit, et al. "Rapid PD-L1 detection in tumors with PET using a highly specific peptide." Biochemical and Biophysical Research Communications 483.1 (2017): 258-263.

Macrocyclic Peptide Citations

"Myristoyl-transportan−LyP-1 tandem peptide was synthesized by CPC Scientific (sequence: myr-GGWTLNSAGYLLGKINLKALAALAKKIL-GGGG-CGNKRTRGC, Cys−Cys bridge). Fluorescently labeled peptide was synthesized bySelleckchem, with a tetramethylrhodamine (TAMRA)-tagged lysine inserted into the glycine spacer. FAM-labeled LyP-1 bearing an azide (azidoacetyl-GGG-cyclo-(EGNKRTRGK)), FAM-labeled LyP-1 bearing a cysteine (C-K(5FAM)-C6-cyclo-(CGNKRTRGC)) and transportan bearing a C-terminal cysteine (myristic acid-GGWTLNSAGYLLGKINLKALAALAKKILC) were synthesized by CPC Scientific, Inc."

1. Lo, Justin H., et al. "A comparison of modular PEG incorporation strategies for stabilization of peptide-siRNA nanocomplexes." Bioconjugate Chemistry (2016).Learn More »

"[RGD-Glu-(DO3A)-6-Ahx-RM2], [Cyclo-(Arg-Gly-Asp-D-Tyr- Lys)-(DO3A)-Glu-(6-Ahx-D-Phe-Gln-Trp-Ala-Val-Gly-His- Sta-Leu-NH2)], was purchased from CPC Scientific (Sunnyvale, CA, USA)."

2. Jiang, Zongrun, et al. "Molecular imaging investigations of a 67Ga/64Cu labeled..ligand,[RGD-Glu-(DO3A)-6-Ahx-RM2], targeting GRPR/αvβ3 biomarkers..” Radiochimica Acta 104.7 (2016): 499-512.Learn More »

"To determine the IC50 values of the selected cyclic peptides, we chemically synthesized the peptides C2 and G12 in both linear and cyclic forms (CPC Scientific)."

3. Young, Travis S., et al. "Evolution of cyclic peptide protease inhibitors." Proceedings of the National Academy of Sciences 108.27 (2011): 11052-11056.Learn More »

"Cyclo-DEYDDPfK; Cyclo-DE(pY)LDPfK; Cyclo-DE(FCOOH)LDPfK (FCOOH= phenylalanine with a carboxyl group at the para position) were purchased either from the MCW facility of the Wisconsin Medical College or from CPC Scientific (San José, CA, USA)"

4. Leone, Marilisa, et al. "Design and NMR Studies of Cyclic Peptides Targeting the N-Terminal Domain of the Protein Tyrosine Phosphatase YopH." Chemical Biology & Drug Design 77.1 (2011): 12-19.Learn More »

"Here, we report the design and characterization of a dually radiolabeled peptide [ 64 Cu]c(RGDfE)K(DOTA)PLGVRY[ 123 I] for targeting cancer cells ... All peptides were purchased from CPC scientific (San Jose, CA.)"

5. Mebrahtu, Efrem, et al. "Initial characterization of a dually radiolabeled peptide for simultaneous monitoring of protein targets and enzymatic activity." Nuclear Medicine and Biology 40.2 (2013): 190-196.Learn More »

"DOTA-[Tyr3]octreotide and NO2A-[Tyr3]octreotide were purchased from CPC Scientific (Sunnyvale, CA)."

6. Lin, Mai, Michael J. Welch, and Suzanne E. Lapi. "Effects of Chelator Modifications on 68Ga-Labeled [Tyr3] Octreotide Conjugates." Molecular Imaging and Biology 15.5 (2013): 606-613.Learn More »

"The synthesized cyclo-(RPKPQQFFGL) peptide and human angiotensin II were purchased from CPC Scientific (CPC Scientific Inc., Sunnyvale, CA, USA)."

7. Zekavat, Behrooz, et al. "Evidence for sequence scrambling and divergent H/D exchange reactions of doubly-charged isobaric b-type fragment ions." J. Am. for Mass Spectrometry 25.2 (2014): 226-236.Learn More »

"Linear and cyclic targeting sequences of the peptides CCVVVT-EG4-GRGDSP-NH2 (97%) (Cap-lRGD) and c[RGDfK(CCVVVT-EG 4 )] (96%) (Cap-cRGD) were purchased from CPC Scientific."

8. Ng, Quinn KT, et al. "Indium-111 labeled gold nanoparticles for in-vivo molecular targeting." Biomaterials 35.25 (2014): 7050-7057.Learn More »

"...4 -c(GX1) 774.9 μM or HYNIC-E-[c(RGDfk)-c(GX1)] 569.5 μM (μg/mL) (CPC Scientific Inc., CA ... 5 /well) were seeded into well culture plates, and it was added the radiotracers 99m Tc-HYNIC-PEG 4 -c ... For nonspecific binding assays, cold conjugate (1 mmol/L/well) was also ..."

9. Oliveira, E. A., and B. L. Faintuch. "Radiolabeling and biological evaluation of the GX1 and RGD-GX1 peptide sequence for angiogenesis targeting." Nuclear Medicine and Biology 42.2 (2015): 123-130.Learn More »

"Methods Radiolabeling Preparation and labeling procedures for HYNIC-PEG4-c(GX1) and HYNIC-E-[c(RGDfk)-c(GX1)] peptides (CPC Scientific Inc., CA, USA) were recently reported by our group (Oliveira and Faintuch 2015)"

10. de Oliveira, Érica Aparecida, et al. "Evaluation of GX1 and RGD-GX1 peptides as new radiotracers for angiogenesis evaluation in experimental glioma models." Amino Acids (2015): 1-11.Learn More »

"DOTA-c(RGDyK) was purchased from CPC Scientific, Inc. (Sunnyvale, CA), and its purity and mass were confirmed at Wake Forest using HPLC and electrospray ionization (ESI) mass spectrometry as described below."

11. Pandya, Darpan N., et al. "Preliminary Therapy Evaluation of 225Ac-DOTA-c (RGDyK) Demonstrates that Cerenkov Radiation Derived from 225Ac Daughter Decay Can Be Detected by Optical Imaging for In Vivo Tumor Visualization." Theranostics 6.5 (2016): 698.Learn More »