Antagomir
Antagomirs, also known as anti-miRs, are a class of chemically engineered oligonucleotides designed to silence endogenous microRNAs (also known as miRNAs or miRs).[1][2][3]
Antagomirs are a kind of antisense oligonucleotide, as their sequence is complementary to their specific miRNA target. Their structure has modifications so as to make them more resistant to degradation. These include 2'-methoxy groups on the ribose sugar, backbones with phosphorothioate bonds, and cholesterol conjugation on the 3' end.[4]
Mechanism of action
[edit]Antagomirs are microRNA inhibitors that bind miRNAs and prevent them from binding to a target mRNA molecule, and the consequent degradation of that mRNA via the RNA-induced silencing complex (RISC). Due to the promiscuity of microRNAs, each of which regulate multiple mRNAs, antagomirs can potentially affect the expression of many different mRNA molecules besides the desired target.
Blockmirs are similarly engineered molecules which, on the other hand, are designed to have a sequence that is complementary to an mRNA sequence that is targeted by a microRNA. Upon binding to an untranslated region of an mRNA, blockmirs sterically block microRNAs from binding to the same site. Because blockmirs bind individual mRNAs and not miRNAs, their activity is more predictable than antagomirs' and less likely to cause off-target effects.[5]
Applications
[edit]Antagomirs are used as a method to constitutively inhibit the activity of specific miRNAs associated with disease. For example, antagomirs against miR-21 have been successfully used to inhibit fibrosis of heart[6] and lung.[7]
HCV
[edit]The primary method for using microRNA technology to target the Hepatitis C Virus (HCV) is by knocking-out the liver-specific microRNA. miRNA-122 binds to the 5' untranslated region of HCV's mRNA strand and, contrary to miRNA's normal function of repressing mRNA, actually upregulates the expression of the Hepatitis C Virus. Thus, the therapeutic goal in such a case would be to keep miRNA-122 from binding to HCV mRNA in order to prevent this mRNA from being expressed. However, miRNA-122 also regulates cholesterol (HDL) and the activity of tumor-suppressor genes (oncogenes).This means that not only will knocking out the microRNA-122 reduce the HCV infection, but it will also reduce the activity of tumor suppressor genes, potentially leading to liver cancer. In order to target HCV mRNA specifically (instead of miRNA-122 as a whole), Blockmir technology has been developed to solely target HCV mRNA, thus avoiding any sort of tampering with oncogene expression. This may be achieved by designing a Blockmir that matches seed 1.[citation needed]
High-density lipoprotein
[edit]MicroRNA-33a/b inhibition in mice leads to increased blood high-density lipoprotein (HDL) levels. Abca1 is essential for production of HDL precursors in liver cells. In macrophages, Abca1 excretes cholesterol from oxidized cholesterol-carrying lipoproteins and thus counteracts atherosclerotic plaques. From this, it is hypothesized that microRNA-33 affects HDL via regulation of Abca1. Therefore, in order to target the regulation of Abca1, a blockmir can be developed that specifically binds to Abca1 mRNA molecules, thus blocking its miRNA site and upregulating its expression. Such an application of blockmir technology could lead to overall increased HDL levels.[citation needed]
Insulin signalling
[edit]MicroRNA-103/107 inhibition in mice leads to increased insulin sensitivity and signalling[8] It has been previously shown that caveolin-1-deficient mice show insulin resistance. MicroRNA-103/107 inhibition in caveolin-1-deficient mice had no effect on insulin sensitivity and signalling. Thus, microRNA-103/107 may affect insulin sensitivity by targeting caveolin-1.[9]
Ischemia and immunotherapy
[edit]The blockmir CD5-2 has been shown to inhibit the interaction between miR-27 and VE-cadherin, enhancing recovery from ischemic injury in mice.[10] The drug has also been shown to enhance T cell infiltration in combination with immunotherapy in mouse models of pancreatic cancer.[11]
References
[edit]- ^ Yue J (July 2011). "miRNA and vascular cell movement". Adv. Drug Deliv. Rev. 63 (8): 616–22. doi:10.1016/j.addr.2011.01.001. PMC 3129380. PMID 21241758.
- ^ Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M (December 2005). "Silencing of microRNAs in vivo with "antagomirs"". Nature. 438 (7068): 685–9. Bibcode:2005Natur.438..685K. doi:10.1038/nature04303. PMID 16258535. S2CID 4414240.
- ^ Czech MP (March 2006). "MicroRNAs as therapeutic targets". N. Engl. J. Med. 354 (11): 1194–5. doi:10.1056/NEJMcibr060065. PMID 16540623.
- ^ Ling, Hui; Calin, George A. (2014-01-01), Dellaire, Graham; Berman, Jason. N.; Arceci, Robert J. (eds.), "Chapter 25 - The Role of MicroRNAs and Ultraconserved Non-Coding RNAs in Cancer", Cancer Genomics, Boston: Academic Press, pp. 435–447, doi:10.1016/b978-0-12-396967-5.00025-6, ISBN 978-0-12-396967-5, retrieved 2022-09-11
- ^ Raghavendra, Pongali; Pullaiah, Thammineni (2018-01-01), Raghavendra, Pongali; Pullaiah, Thammineni (eds.), "Chapter 2 - RNA-Based Applications in Diagnostic and Therapeutics for Cancer", Advances in Cell and Molecular Diagnostics, Academic Press, pp. 33–55, doi:10.1016/b978-0-12-813679-9.00002-6, ISBN 978-0-12-813679-9, retrieved 2022-09-11
- ^ Adam O, Löhfelm B, Thum T, Gupta SK, Puhl SL, Schäfers HJ, Böhm M, Laufs U (September 2012). "Role of miR-21 in the pathogenesis of atrial fibrosis". Basic Res. Cardiol. 107 (5): 278. doi:10.1007/s00395-012-0278-0. PMID 22760500. S2CID 8911862.
- ^ Pandit KV, Corcoran D, Yousef H, Yarlagadda M, Tzouvelekis A, Gibson KF, Konishi K, Yousem SA, Singh M, Handley D, Richards T, Selman M, Watkins SC, Pardo A, Ben-Yehudah A, Bouros D, Eickelberg O, Ray P, Benos PV, Kaminski N (July 2010). "Inhibition and role of let-7d in idiopathic pulmonary fibrosis". Am. J. Respir. Crit. Care Med. 182 (2): 220–9. doi:10.1164/rccm.200911-1698OC. PMC 2913236. PMID 20395557.
- ^ Kahn CR (December 1978). "Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction". Metab. Clin. Exp. 27 (12 Suppl 2): 1893–902. doi:10.1016/S0026-0495(78)80007-9. PMID 723640.
- ^ Trajkovski M, Hausser J, Soutschek J, Bhat B, Akin A, Zavolan M, Heim MH, Stoffel M (June 2011). "MicroRNAs 103 and 107 regulate insulin sensitivity". Nature. 474 (7353): 649–53. doi:10.1038/nature10112. PMID 21654750. S2CID 2060531.
- ^ Young, J. A.; Ting, K. K.; Li, J.; Moller, T.; Dunn, L.; Lu, Y.; Lay, A. J.; Moses, J.; Prado-Lourenco, L.; Khachigian, L. M.; Ng, M.; Gregory, P. A.; Goodall, G. J.; Tsykin, A.; Lichtenstein, I.; Hahn, C. N.; Tran, N.; Shackel, N.; Kench, J. G.; McCaughan, G.; Vadas, M. A.; Gamble, J. R. (5 September 2013). "Regulation of vascular leak and recovery from ischemic injury by general and VE-cadherin-restricted miRNA antagonists of miR-27". Blood. 122 (16): 2911–2919. doi:10.1182/blood-2012-12-473017. PMID 24009229.
- ^ Zhao, Yang; Ting, Kaka; Li, Jia; Cogger, Victoria C; Chen, Jinbiao; Johansson-Percival, Anna; Ngiow, Shin Foong; Holst, Jeff; Grau, Georges E. R.; Goel, Shom; Moller, Thorleif; Dejana, Elisabetta; McCaughan, Geoffrey W; Smyth, Mark J.; Ganss, Ruth; Vadas, Mathew A; Gamble, Jennifer R (27 June 2017). "Targeting vascular endothelial-cadherin in tumor-associated blood vessels promotes T cell-mediated immunotherapy". Cancer Research. 77 (16): 4434–4447. doi:10.1158/0008-5472.CAN-16-3129. PMID 28655790.