The synthesis of the linear RP-182 analog, bicyclo[6.1.0]non-4-yn-9-ylmethyloxycarbonyl-PEG2-Lys-Phe-Arg-Lys-Ala-Phe-Lys-Arg-Phe-Phe-Lys(azido-PEG)-NH2, was achieved using standard solid-phase peptide synthesis (SPPS) protocols. After cleaving the linear peptide from the resin, macrocyclization was performed in the liquid phase through a strain-promoted click reaction. BCN introduces extra ring strain due to its fused cyclopropane structure. The combined effect of ring strain, the selection of BCN, and copper catalysis significantly increases the macrocyclization efficiency of longer peptides like RP-182.
Stapled peptides have emerged as a powerful tool in drug discovery and therapeutic development due to their ability to overcome the limitations associated with traditional peptide drugs, such as poor stability and low cell permeability. By introducing staples into the peptide backbone, researchers can stabilize peptide conformations and enhance their interactions with target proteins, resulting in improved efficacy and specificity. This approach not only addresses the challenges of peptide drug design but also opens new avenues for targeting challenging biomolecular interactions that are difficult to modulate with small molecules or antibodies. The development of stapled peptides has led to significant advancements in targeting protein-protein interactions, addressing previously intractable diseases, and enhancing the precision of therapeutic interventions.
Singh, S.S., Calvo, R., Kumari, A., Sable, R.V., Fang, Y., Tao, D., Hu, X., Castle, S.G., Nahar, S., Li, D. and Major, E. Molecular Cancer Therapeutics (2024).
- CPC Scientific Inc., 160E Tasman Dr., Suite 200, San Jose, CA 95134
[..] assembling the peptide on the Rink Amide resin and attaching the PEG azide moiety to the N-terminal Lys, the Dde group was removed as previously shown and coupled to the Fmoc-PEG2-acid. Removal of the Fmoc followed by simultaneously click/coupling to bicyclo[6.1.0]non-4-yn-9-ylmethyl (2,5-dioxopyrrolidin-1-yl) carbonate gave 1c which was deprotected and cleaved from the resin to give 1c.
Quigley, Neil Gerard, Katja Steiger, Stefanie Felicitas Färber, Frauke Richter, Wilko Weichert, and Johannes Notni. Molecular Pharmaceutics (2024), 21(4), 1827-1837.
… by positron emission tomography (PET) imaging and ex vivo … clinical PD-L1 PET imaging because it detects even very low … The peptide WL12 was purchased from CPC Scientific (San …
Lopez, Andrea, Denis E. Reyna, Nadege Gitego, Felix Kopp, Hua Zhou, Miguel A. Miranda-Roman, Lars Ulrik Nordstrøm et al. Nature Communications 13, no. 1 (2022): 1-18.
"Hydrocarbon-stapled peptide corresponding to the BH3 domain of BIM, FITC-BIM SAHBA2: FITC-βAla-EIWIAQELRS5IGDS5F’NAYYA-CONH2, where S5 represents the non-natural amino acid inserted for olefin metathesis, was synthesized, purified at >95% purity by CPC Scientific Inc."
Axiak-Bechtel, Sandra M., Stacey B. Leach, David G. Scholten, Jessica R. Newton-Northup, Brendan J. Johnson, H. E. Durham, Kenneth A. Gruber, and Michael F. Callahan. Pharmacology Research & Perspectives 9, no. 3 (2021): e00777.
TCMCB07 [a cyclic substituted melanocortin antagonist with the structure Ac- Nle- cyclo[Asp- Pro- DNal(2’)-Arg- Trp- Lys]- DVal- DPro- NH2] was manufactured by CPC Scientific Inc. under cGMP conditions. Active pharmaceutical ingredient was dissolved in milliQ water at 10 mg ml−1, sterile filtered [..]”
Ramasubramanian, Anusuya, Riya Muckom, Caroline Sugnaux, Christina Fuentes, Barbara L. Ekerdt, Douglas S. Clark, Kevin E. Healy, and David V. Schaffer. ACS Biomaterials Science & Engineering 7, no. 4 (2021): 1344-1360.
A cyclic 11-MUA adhesion peptide (CPC Scientific Inc., Sunnyvale, CA) was also synthesized via standard Fmoc chemistry and cyclized via a lactam bond between Asp(1) and Lys(9) to form (11-MUA)-GG-PEG 2 -cyclo(DMGDGRPRK)-NH 2 or 11-MUA-cyclic (7C-1).
GhavamiNejad, A.; Lu, B.; Samarikhalaj, M.; Liu, J. F.; Mirzaie, S.; Pereira, S.; Zhou, L.; Giacca, A.; Wu, X. Y., Drug Delivery and Translational Research 2021, 1-13.
"PRL-2903 (PRL) was synthesized and purchased from CPC Scientific Inc. (San Jose, CA, USA)."
DePalma, S. J.; Davidson, C. D.; Stis, A. E.; Helms, A. S.; Baker, B. M., Biomaterials Science, 2021, 9 (1), 93-107.
.. matrices were functionalized with cell adhesive peptides.. Gly-Phe-Hyp-Gly-Glu-Arg (GFOGER; CPC Scientific) via Michael-Type addition to available vinyl sulfone groups."
Abdulganiyyu, I. A.; Kaczmarek, K.; Zabrocki, J.; Nachman, R. J.; Marchal, E.; Schellens, S.; Verlinden, H.; Broeck, J. V.; Marco, H.; Jackson, G. E. Insect Biochemistry and Molecular Biology 2020, 103362.
A head-to-tail cyclic, octapeptide analog of Locmi-AKH-I, cycloAKH (cyclo[LNFTPNWG]) was synthesized to severely restrict the conformational freedom of the AKH structure.
