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Targeting Intracellular Protein-Protein Interactions with Macrocyclic Peptides
Abstract: Potent, selective, cell-permeable, and metabolically stable macrocyclic peptides (including mono- and bicyclic peptides) have been developed to target intracellular protein-protein interactions (PPIs), by leveraging a novel class of highly active cyclic cell-penetrating peptides (CPPs). In the first approach, potent PPI inhibitors such as linear peptides, stapled peptides, and cyclic peptides, which are generally impermeable to the cell membrane, are rendered cell-permeable and biologically active by conjugating them to a cyclic CPP. In an alternative approach, cell-permeable macrocyclic peptidyl PPI inhibitors are designed to have their target-binding and cell-penetrating motifs integrated into the same peptide sequence. The validity of these approaches has been demonstrated by the development of macrocyclic peptidyl inhibitors against some of the most challenging PPI targets, including the calcineurin-NFAT, CAL-CFTR, and Ras-Raf interactions. These inhibitors have demonstrated excellent in vitro and/or in vivo efficacy for the treatment of inflammatory diseases, cystic fibrosis, and cancer in animal models. |
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Related publications:
Dougherty, P. G., Karpurapu, M., Koley, A., Lukowski, J. K., Qian, Z., Srinivas Nirujogi, T., Rusu, L., Chung, S., Hummon, A. B., Li, H. W., Christman, J. W., and Pei, D. (2020) A Peptidyl Inhibitor that Blocks Calcineurin-NFAT Interaction and Prevents Acute Lung Injury. J. Med. Chem. 63, 12853–12872.
Dougherty, P. G., Wellmerling, J. H., Koley, A., Lukowski, J. K., Hummon, A. B., Cormet-Boyaka, E., and Pei, D. (2020) Cyclic Peptidyl Inhibitors against CAL-CFTR Interaction for Treatment of Cystic Fibrosis. J. Med. Chem. 63, 15773–15784.
Buyanova, M., Cai, S., Cooper, J., Rhodes, C., Salim, H., Sahni, A., Upadhyaya, P., Yang, R., Sarkar, A., Li, N., Wang, Q. E., & Pei, D. (2021) Discovery of a Bicyclic Peptidyl Pan-Ras Inhibitor. J. Med. Chem. 64, 13038–13053.
Dougherty, P. G., Karpurapu, M., Koley, A., Lukowski, J. K., Qian, Z., Srinivas Nirujogi, T., Rusu, L., Chung, S., Hummon, A. B., Li, H. W., Christman, J. W., and Pei, D. (2020) A Peptidyl Inhibitor that Blocks Calcineurin-NFAT Interaction and Prevents Acute Lung Injury. J. Med. Chem. 63, 12853–12872.
Dougherty, P. G., Wellmerling, J. H., Koley, A., Lukowski, J. K., Hummon, A. B., Cormet-Boyaka, E., and Pei, D. (2020) Cyclic Peptidyl Inhibitors against CAL-CFTR Interaction for Treatment of Cystic Fibrosis. J. Med. Chem. 63, 15773–15784.
Buyanova, M., Cai, S., Cooper, J., Rhodes, C., Salim, H., Sahni, A., Upadhyaya, P., Yang, R., Sarkar, A., Li, N., Wang, Q. E., & Pei, D. (2021) Discovery of a Bicyclic Peptidyl Pan-Ras Inhibitor. J. Med. Chem. 64, 13038–13053.
