Antagomir

Antagomirs also known as anti-miRs or blockmirs are a class of chemically engineered oligonucleotides that prevent other molecules from binding to a desired site on an mRNA molecule. Antagomirs are used to silence endogenous microRNA (miR). Antagomirs also known as anti-miRs or blockmirs are a class of chemically engineered oligonucleotides that prevent other molecules from binding to a desired site on an mRNA molecule. Antagomirs are used to silence endogenous microRNA (miR). An antagomir is a small synthetic RNA that is perfectly complementary to the specific miRNA target with either mispairing at the cleavage site of Ago2 or some sort of base modification to inhibit Ago2 cleavage. Usually, antagomirs have some sort of modification, such as 2'-methoxy groups and phosphorothioates, to make them more resistant to degradation. Antagomirs are microRNA inhibitors that inhibit miRNAs but, because of the promiscuity of microRNAs, antagomirs could affect the regulation of many different mRNA molecules. It is unclear how antagomirization (the process by which an antagomir inhibits miRNA activity) operates, but it is believed to inhibit by irreversibly binding the mRNA. Blockmirs are designed to have a sequence that is complementary to an mRNA sequence that serves as a binding site for microRNA. Upon binding, Blockmirs sterically block microRNA from binding to the same site, which prevents the degradation of the target mRNA via RNA-induced silencing complex (RISC). If a Blockmir binds to a non-intended RNA, it will only cause an effect if it prevents binding of a microRNA or another cellular factor. This occurrence is highly unlikely, meaning off-target effects will rarely be an issue. Hence, Blockmirs enable modulation of microRNA-based gene regulation with exquisite specificity. Importantly, Blockmirs are typically agonists of their target mRNA, i.e. they increase the synthesis of the protein encoded by the target mRNA. Blockmirs bind on the 3’ end of the untranslated region (UTR) of the mRNA strand, which adequately blocks microRNA from binding, as most microRNAs do not bind to the translated region. Antagomirs are used as a method to constitutively inhibit the activity of specific miRNAs. For example, antagomirs against miR-21 have been successfully used to inhibit fibrosis of heart and lung. microRNA-122, cholesterol and Hepatitis C Virus (HCV) The primary method for using microRNA technology to target HCV is by knocking out the liver-specific microRNA. miRNA-122 binds to the 5' UTRregion 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. microRNA-33a/b