Elamipretide
Elamipretide also known as SS-31 (Szeto-Schiller 31), MTP-131 and Bendavia is a small cell-permeable tetrapeptide (D-Arg-dimethylTyr-Lys-Phe-NH2) which is a member of the Szeto-Schiller (SS) peptides known to selectively target the inner mitochondrial membrane.[1][2] SS-31 binds selectively to cardiolipin that prevents cardiolipin from converting cytochrome c into a peroxidase while protecting its electron carrying function. This optimizes mitochondrial electron transport and ATP synthesis and prevents ROS production at the electron transport chain.[3] As a result, SS-31 protects the structure of mitochondrial cristae and promotes oxidative phosphorylation. SS-31 represents a class of compounds that can recharge the cellular powerhouse and restore bioenergetics.[4]
Elamipretide is a pharmacologic agent the effect of which on mitochondria makes it possible to improve physiological parameters in mitochondrial myopathies and in aging.[5][6] .Treatment with SS-31 SS-31 reversed age-related decline in maximum mitochondrial ATP production (ATPmax) and coupling of oxidative phosphorylation (P/O); restores redox homeostasis, improves mitochondrial quality, and increases exercise tolerance in aged mice without an increase in mitochondrial content.[7][8][9][10]
In animal models of myocardial infarction and ischemia–reperfusion injury elamipretide yielded promising results, showing reduced infarct size and improved left ventricular (LV) contractile function,[11][12][13][14] in particular by suppressing cardiac fibrosis in the border zone of the infarcted heart,[15]
However, elamipretide has failed to show promising results in clinical trials in patients with various heart failure phenotypes (NCT02814097, NCT02914665, NCT02788747). This could be explained by the quick degradation of the peptide in the bloodstream, although some modifications have been made to reduce the degradation of this peptide, such as a switch from an L-amino acid to a D-amino acid in the first position to make it resistant to aminopeptidase activity and a C-terminal amidation to reduce hydrolysis.[5] In addition it has been developed bioconjugates of elamipretide to form elamipretide decorated nanoparticles.[16]
Elamipretide has also improved mitochondrial function in kidneys in large animal studies.[17]
References
- ↑ Zhao, K., Zhao, G. M., Wu, D., Soong, Y., Birk, A. V., Schiller, P. W., & Szeto, H. H. (2004). Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. The Journal of biological chemistry, 279(33), 34682-34690. PMID: 15178689 DOI: 10.1074/jbc.M402999200
- ↑ Szeto, H. H., & Schiller, P. W. (2011). Novel therapies targeting inner mitochondrial membrane—from discovery to clinical development. Pharmaceutical research, 28, 2669-2679. PMID: 21638136 DOI: 10.1007/s11095-011-0476-8
- ↑ Birk, A. V., Chao, W. M., Bracken, C., Warren, J. D., & Szeto, H. H. (2014). Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. British journal of pharmacology, 171(8), 2017-2028. PMID: 24134698 PMCID: PMC3976619 DOI: 10.1111/bph.12468
- ↑ Szeto, H. H. (2014). First‐in‐class cardiolipin‐protective compound as a therapeutic agent to restore mitochondrial bioenergetics. British journal of pharmacology, 171(8), 2029-2050. PMID: 24117165 PMCID: PMC3976620 DOI: 10.1111/bph.12461
- ↑ 5.0 5.1 Whitson, J. A., Bitto, A., Zhang, H., Sweetwyne, M. T., Coig, R., Bhayana, S., ... & Rabinovitch, P. S. (2020). SS‐31 and NMN: Two paths to improve metabolism and function in aged hearts. Aging Cell, 19(10), e13213. PMID: 32779818 PMCID: PMC7576234 DOI: 10.1111/acel.13213
- ↑ Sabbah, H. N., Gupta, R. C., Kohli, S., Wang, M., Hachem, S., & Zhang, K. (2016). Chronic therapy with elamipretide (MTP-131), a novel mitochondria-targeting peptide, improves left ventricular and mitochondrial function in dogs with advanced heart failure. Circulation: Heart Failure, 9(2), e002206. PMID: 26839394 PMCID: PMC4743543 DOI: 10.1161/CIRCHEARTFAILURE.115.002206
- ↑ Campbell, M. D., Duan, J., Samuelson, A. T., Gaffrey, M. J., Merrihew, G. E., Egertson, J. D., ... & Marcinek, D. J. (2019). Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice. Free Radical Biology and Medicine, 134, 268-281. PMID: 30597195 PMCID: PMC6588449 DOI: 10.1016/j.freeradbiomed.2018.12.031
- ↑ Siegel, M. P., Kruse, S. E., Percival, J. M., Goh, J., White, C. C., Hopkins, H. C., ... & Marcinek, D. J. (2013). Mitochondrial‐targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging cell, 12(5), 763-771. PMID: 23692570 PMCID: PMC3772966 DOI: 10.1111/acel.12102
- ↑ Campbell, M. D., Samuelson, A. T., Chiao, Y. A., Sweetwyne, M. T., Ladiges, W. C., Rabinovitch, P. S., & Marcinek, D. J. (2023). Intermittent treatment with elamipretide preserves exercise tolerance in aged female mice. GeroScience, 1-11. PMID: 36840897 DOI: 10.1007/s11357-023-00754-0
- ↑ Nickel, K., Zhu, L., Mangalindan, R., Snyder, J. M., Tucker, M., Whitson, J., ... & Ladiges, W. (2022). Long-term treatment with Elamipretide enhances healthy aging phenotypes in mice. Aging pathobiology and therapeutics, 4(3), 76-83. PMID: 36250163 PMCID: PMC9562127 DOI: 10.31491/apt.2022.09.089
- ↑ Dai, W., Shi, J., Gupta, R. C., Sabbah, H. N., Hale, S. L., & Kloner, R. A. (2014). Bendavia, a mitochondria-targeting peptide, improves postinfarction cardiac function, prevents adverse left ventricular remodeling, and restores mitochondria-related gene expression in rats. Journal of cardiovascular pharmacology, 64(6), 543-553. PMID: 25165999 DOI: 10.1097/FJC.0000000000000155
- ↑ Sabbah, H. N., Gupta, R. C., Kohli, S., Wang, M., Hachem, S., & Zhang, K. (2016). Chronic therapy with elamipretide (MTP-131), a novel mitochondria-targeting peptide, improves left ventricular and mitochondrial function in dogs with advanced heart failure. Circulation: Heart Failure, 9(2), e002206. PMID: 26839394 PMCID: PMC4743543 DOI: 10.1161/CIRCHEARTFAILURE.115.002206
- ↑ Werbner, B., Tavakoli-Rouzbehani, O. M., Fatahian, A. N., & Boudina, S. (2023). The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease, aging, and heart failure. The journal of cardiovascular aging, 3(1). PMID: 36742465 PMCID: PMC9894375 DOI: 10.20517/jca.2022.42
- ↑ Brown, D. A., Hale, S. L., Baines, C. P., Rio, C. L. D., Hamlin, R. L., Yueyama, Y., ... & Kloner, R. A. (2014). Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia. Journal of cardiovascular pharmacology and therapeutics, 19(1), 121-132. PMID: 24288396 PMCID: PMC4103197 DOI: 10.1177/1074248413508003
- ↑ Shi, J., Dai, W., Hale, S. L., Brown, D. A., Wang, M., Han, X., & Kloner, R. A. (2015). Bendavia restores mitochondrial energy metabolism gene expression and suppresses cardiac fibrosis in the border zone of the infarcted heart. Life sciences, 141, 170-178. PMID: 26431885 PMCID: PMC4973309 DOI: 10.1016/j.lfs.2015.09.022
- ↑ Gendron, A., Domenichini, S., Zanna, S., Gobeaux, F., Piesse, C., Desmaële, D., & Varna, M. (2023). Development and Characterization of Innovative Multidrug Nanoformulation for Cardiac Therapy. Materials, 16(5), 1812. PMID: 36902927 PMCID: PMC10003764 DOI: 10.3390/ma16051812
- ↑ Zhu, Y., Luo, M., Bai, X., Li, J., Nie, P., Li, B., & Luo, P. (2022). SS-31, a mitochondria-targeting peptide, ameliorates kidney disease. Oxidative Medicine and Cellular Longevity, 2022. PMID: 35707274 PMCID: PMC9192202 DOI: 10.1155/2022/1295509
