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.
Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists.
Chandramohan, A., Josien, H., Yuen, T.Y., Duggal, R., Spiegelberg, D., Yan, L., Juang, Y.C.A., Ge, L., Aronica, P.G., Kaan, H.Y.K. and Lim, Y.H. Nature Communications 15, no. 1 (2024): 489.
- Merck & Co., Inc., Kenilworth, NJ 07033, USA.
- Merck & Co., Inc., Boston, MA 02115, USA
- Merck & Co., Inc., West Point, PA 19486, USA
- Genentech, South San Francisco, CA 94080, USA
We thank Evans (Chen) Ge, Mike (Dixin) Xue, and Simon (Junhua) Li at Chinese Peptide Company (CPC) for peptide synthesis support.
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."
Spitz, A. Z.; Zacharioudakis, E.; Reyna, D. E.; Garner, T. P.; Gavathiotis, E., Nature Communications 2021, 12 (1), 1-15.
Hydrocarbon-stapled peptides corresponding to the BH3 domain of BIM, BIM SAHB: FITC-Ahx-EIWIAQELRS5IGDS5FNAYYA-CONH, where S5 represents the non-natural amino acid inserted for olefin metathesis, were synthesized and purified at >95% purity by CPC Scientific Inc.
Curreli, Francesca, Sofia MB Victor, Shahad Ahmed, Aleksandra Drelich, Xiaohe Tong, Chien-Te K. Tseng, Christopher D. Hillyer, and Asim K. Debnath. Mbio 11, no. 6 (2020): e02451-20.
We have synthesized (CPC Scientific, Inc.) four stapled peptides, as depicted in Figure 2. We also synthesized the linear peptide, NYBSP-C, as a control. Besides, we purchased a linear peptide, SBP1, to use as a control, which was reported recently to bind to SARS-CoV-2 RBD with high affinity (KD = 47nM).
Marion, Vincent, and Nikolai Petrovsky. U.S. Patent Application 16/627,389, filed July 9, 2020.
H-VECTM-R8-EKRVLA-S5-LDKPPFLTQLHS-OH (SEQ ID NO: 21) [..] H-VECTM-R8-EKRVLA-S5-LDKPPFLTQLHS-NH2 [..]
Garner, Thomas P., Dulguun Amgalan, Denis E. Reyna, Sheng Li, Richard N. Kitsis, and Evripidis Gavathiotis. Nature Chemical Biology 15, no. 4 (2019): 322.
"Hydrocarbon-stapled peptides corresponding to the BH3 domain of BIM, BIM SAHBA2: N-acetylated- and FITC-Ahx-EIWIAQELRS5IGDS5FNAYYA-CONH2, where S5 represents the non-natural amino acid inserted for olefin metathesis, were synthesized, purified at >95% purity by CPC Scientific Inc. and characterized as previously described."
Gavathiotis, E., Albert Einstein College of Medicine, 2017. U.S. Patent Application 15/311,861.
"Hydrocarbon-stapled peptide corresponding to the BH3 domain of BIM, BIM SAHBA2: N-acetylated 145EIWIAQELRS5IGDS5FNAYYA164-CONH2 (SEQ ID NO:2), where S5 represents the non-natural amino acid inserted for olefin metathesis, was synthesized, purified and characterized as previously described by CPC Scientific (11)."
Garner, Thomas P., et al. Molecular Cell 63.3 (2016): 485-497.
"Hydrocarbon-stapled peptide corresponding to the BH3 domain of BIM, BIM SAHBA: N-acetylated 145EIWIAQELRS5IGDS5FNAYYA164-CONH2, where S5 represents the non-natural amino acid inserted for olefin metathesis, was synthesized, purified and characterized as previously described by CPC Scientific (Gavathiotis et al., 2008)."
